ERF

Chr 19AD

ETS2 repressor factor

ENSG00000105722UniProt: P50548

Potent transcriptional repressor that binds to the H1 element of the Ets2 promoter. May regulate other genes involved in cellular proliferation. Required for extraembryonic ectoderm differentiation, ectoplacental cone cavity closure, and chorioallantoic attachment (By similarity). May be important for regulating trophoblast stem cell differentiation (By similarity)

Primary Disease Associations & Inheritance

Chitayat syndromeMIM #617180
AD
Craniosynostosis 4MIM #600775
AD
304
ClinVar variants
69
Pathogenic / LP
0.99
pLI score· haploinsufficient
9
Active trials
Clinical Summary— ERF
🧬
Gene-Disease Validity (ClinGen)
craniosynostosis 4 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
69 Pathogenic / Likely Pathogenic· 152 VUS of 304 total submissions
💊
Clinical Trials
9 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.26LOEUF
pLI 0.990
Z-score 3.73
OE 0.06 (0.02–0.26)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.25Z-score
OE missense 0.66 (0.60–0.74)
238 obs / 358.1 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.06 (0.02–0.26)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.66 (0.60–0.74)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.18
0≤1.21.6
LoF obs/exp: 1 / 18.2Missense obs/exp: 238 / 358.1Syn Z: -1.84

ClinVar Variant Classifications

304 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic40
Likely Pathogenic29
VUS152
Likely Benign60
Benign15
Conflicting8
40
Pathogenic
29
Likely Pathogenic
152
VUS
60
Likely Benign
15
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
13
2
25
0
40
Likely Pathogenic
15
4
10
0
29
VUS
6
137
8
1
152
Likely Benign
0
13
7
40
60
Benign
0
1
3
11
15
Conflicting
—8
Total341575352304

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ERF · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ERF-related complex craniosynostosis

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

ERF-related Chitayat syndrome: hyperphalangism, characteristic facies, hallux valgus and bronchomalacia

definitive
ADGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Chitayat syndrome

MIM #617180

Molecular basis of disorder known

Autosomal dominant

Craniosynostosis 4

MIM #600775

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Single-cell transcriptomes and chromatin accessibility of endothelial cells unravel transcription factors associated with dysregulated angiogenesis in systemic sclerosis.
Huang M et al.·Ann Rheum Dis
2024
Clinical genetics of craniosynostosis.
Wilkie AOM et al.·Curr Opin Pediatr
2017Review
Loss-of-function variants in ERF are associated with a Noonan syndrome-like phenotype with or without craniosynostosis.
Dentici ML et al.·Eur J Hum Genet
2024
Missense and truncated variants in ERF in individuals with a Noonan-like phenotype without craniosynostosis.
Goto Y et al.·Sci Rep
2025
Noonan syndrome-like phenotype associated with an ERF frameshift variant.
Hirano Y et al.·Am J Med Genet A
2024Case report
ERF-related craniosynostosis and surgical management in the paediatric cohort.
Afshari FT et al.·Childs Nerv Syst
2023Cohort
Deletion of ERF and CIC causes abnormal skull morphology and global developmental delay.
Singh R et al.·Cold Spring Harb Mol Case Stud
2021
Cognitive, Behavioural, Speech, Language and Developmental Outcomes Associated with Pathogenic Variants in the ERF Gene.
Care H et al.·J Craniofac Surg
2022
Pearls and pitfalls in brain functional analysis by event-related potentials: a narrative review by the Italian Psychophysiology and Cognitive Neuroscience Society on methodological limits and clinical reliability-part I.
de Tommaso M et al.·Neurol Sci
2020Review
Esophagorespiratory Fistulas: Survival and Outcomes of Treatment.
Lenz CJ et al.·J Clin Gastroenterol
2018
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
AP2/ERF Transcription Factor MiRAP2.11 Mediates Ethylene-Induced Starch Degradation in Postharvest Mango Fruit.
Liu J et al.·J Agric Food Chem
2026
A genome-wide study of the AP2/ERF gene family in mangrove Avicennia marina reveals the role of AmERF1 in salt tolerance through mediating proline biosynthesis and H₂O₂ homeostasis.
Liu J et al.·Plant Sci
2026
The AP2/ERF transcription factor CsRAV1 represses CsGL2 to regulate the trichome development of tea plants.
Yi XQ et al.·Plant Physiol Biochem
2026
Genome-wide analysis of Alfalfa AP2/ERF gene family and abiotic stress response.
Qiu R et al.·Front Plant Sci
2026🔓 Open Access
Genome-Wide Characterisation of the AP2/ERF Family in Salvia miltiorrhiza Identifies Hormone-Responsive Candidates Associated with Phenolic Acid Accumulation.
Chen S et al.·Int J Mol Sci
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Melanoma

Clinical Study of Fianlimab in Combination With Cemiplimab Versus Pembrolizumab in Adolescent and Adult Patients With Previously Untreated Unresectable Locally Advanced or Metastatic Melanoma

ACTIVE NOT RECRUITING
NCT05352672Phase PHASE3Regeneron PharmaceuticalsStarted 2022-07-14
FianlimabCemiplimabPembrolizumab
Malignant Melanoma Stage II

Adjuvant Nivolumab Treatment in Stage II (IIA, IIB, IIC) High-risk Melanoma

ACTIVE NOT RECRUITING
NCT04309409Phase PHASE3University Hospital, EssenStarted 2020-07-01
Nivolumab
Basal Cell Carcinoma (BCC)First Line Treatment

Evaluation of Efficacy and Safety of Cemiplimab as First Line Treatment for Advanced Basal Cell Carcinoma (BCC) Patients

RECRUITING
NCT06981325Phase PHASE2Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus NordwestStarted 2025-08-07
Cemiplimab
Healthy AdultsHigh AltitudeIsolation, Social

Human Milk Oligosaccharides (HMOs) and Gut Microbiota, Immune System in Antarctica

ENROLLING BY INVITATION
NCT06133530Phase NAIU University of Applied SciencesStarted 2023-09-24
Human milk oligosaccharidesMaltose
Acute Coronary Syndrome

A Study of Milvexian in Participants After a Recent Acute Coronary Syndrome

ACTIVE NOT RECRUITING
NCT05754957Phase PHASE3Janssen Research & Development, LLCStarted 2023-04-07
MilvexianPlacebo
Advanced (Stage IIIB/IV) Non-small Cell Lung Cancer (NSCLC) With MET Exon 14 (METex14) Skipping Alterations or MET AmplificationLung Adenocarcinoma Stage IIIB/IV

Tepotinib Phase II in NSCLC Harboring MET Alterations (VISION)

ACTIVE NOT RECRUITING
NCT02864992Phase PHASE2EMD Serono Research & Development Institute, Inc.Started 2016-09-13
Tepotinib
Carcinoma, Non-Small-Cell LungNeoplasm Metastasis

A Study of First-Line Olomorasib (LY3537982) and Pembrolizumab With or Without Chemotherapy in Patients With Advanced KRAS G12C-Mutant Non-small Cell Lung Cancer

RECRUITING
NCT06119581Phase PHASE3Eli Lilly and CompanyStarted 2023-12-21
LY3537982PembrolizumabPlacebo
Melanoma

A Clinical Trial of Three Study Medicines (Encorafenib, Binimetinib, and Pembrolizumab) in Patients With Advanced or Metastatic Melanoma

ACTIVE NOT RECRUITING
NCT04657991Phase PHASE3PfizerStarted 2021-01-15
EncorafenibBinimetinibPembrolizumab
Melanoma

A Trial to See if the Combination of Fianlimab With Cemiplimab Works Better Than Pembrolizumab for Preventing or Delaying Melanoma From Coming Back After it Has Been Removed With Surgery

ACTIVE NOT RECRUITING
NCT05608291Phase PHASE3Regeneron PharmaceuticalsStarted 2023-01-16
FianlimabCemiplimabPembrolizumab

External Resources

Links to major genomics databases and tools