ERF

Chr 19AD

ETS2 repressor factor

Also known as: CHYTS, CRS4, PE-2, PE2

NCBI Gene: 2077 ENSG00000105722 UniProt: P50548 OMIM: 611888

ERF encodes a transcriptional repressor that binds to the ETS2 promoter and regulates genes involved in cellular proliferation and trophoblast differentiation. Mutations cause Chitayat syndrome and craniosynostosis 4, both inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants (pLI 0.99), indicating that haploinsufficiency is likely not tolerated in the general population.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

ETS2 is a transcription factor and protooncogene involved in development, apoptosis, and the regulation of telomerase. The protein encoded by this gene binds to the ETS2 promoter and is a strong repressor of ETS2 transcription. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.262 OMIM phenotypes

Clinical Summary— ERF

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Gene-Disease Validity (ClinGen)

craniosynostosis 4 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

59 unique Pathogenic / Likely Pathogenic· 157 VUS of 303 total submissions

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Clinical Trials

8 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

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?

LoF OE?0.06 (0.02–0.26)

0≤0.351.4

Missense OE?0.66 (0.60–0.74)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 1 / 18.2Missense obs/exp: 238 / 358.1Syn Z: -1.84

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveERF-related complex craniosynostosisLOFAD

definitiveERF-related Chitayat syndrome: hyperphalangism, characteristic facies, hallux valgus and bronchomalaciaGOFAD

This gene — mechanism propensity

0.3693th %ile

GOF

0.3590th %ile

LOF

0.82top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 85% of P/LP variants are LoF · LOEUF 0.26 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

LOFHeterozygous intragenic loss-of-function mutations of ERF, encoding an ETS transcription factor, were previously reported to cause a novel craniosynostosis syndrome, suggesting that ERF is haploinsufficient.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 33993607 ↗

ClinVar Variant Classifications

303 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29

Likely Pathogenic30

VUS157

Likely Benign60

Benign15

Conflicting8

Pathogenic

Likely Pathogenic

157

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	24	3	2	0	29
Likely Pathogenic	26	4	0	0	30
VUS	8	145	3	1	157
Likely Benign	0	14	6	40	60
Benign	0	1	3	11	15
Conflicting	—				8
Total	58	167	14	52	299

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap ERF — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

ERF · protein map & ClinVar variants

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

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

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

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

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

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

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

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

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

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

Clinical Literature

Open Research Assistant →

Landmark / reviewRecent case evidence

Full-Text Mentions

NLP-detected gene mentions in article bodies · via PubTator3

PubTator3

Comparative and expression analyses of AP2/ERF genes reveal copy number expansion and potential functions of ERF genes in Solanaceae

Choi JW et al.·BMC Plant Biol

2023