HERC1

Chr 15AR

HECT and RLD domain containing E3 ubiquitin protein ligase family member 1

NCBI Gene: 8925ENSG00000103657UniProt: Q15751

Involved in membrane trafficking via some guanine nucleotide exchange factor (GEF) activity and its ability to bind clathrin. Acts as a GEF for Arf and Rab, by exchanging bound GDP for free GTP. Binds phosphatidylinositol 4,5-bisphosphate, which is required for GEF activity. May also act as a E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates

Primary Disease Associations & Inheritance

Macrocephaly, dysmorphic facies, and psychomotor retardationMIM #617011
AR
558
ClinVar variants
11
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— HERC1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
11 Pathogenic / Likely Pathogenic· 361 VUS of 558 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.24LOEUF
pLI 1.000
Z-score 11.79
OE 0.19 (0.15–0.24)
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.
4.96Z-score
OE missense 0.72 (0.69–0.75)
1838 obs / 2541.0 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.19 (0.15–0.24)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.72 (0.69–0.75)
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.1.02
0≤1.21.6
LoF obs/exp: 46 / 245.4Missense obs/exp: 1838 / 2541.0Syn Z: -0.59

ClinVar Variant Classifications

558 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7
Likely Pathogenic4
VUS361
Likely Benign175
Benign8
Conflicting3
7
Pathogenic
4
Likely Pathogenic
361
VUS
175
Likely Benign
8
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
0
5
0
7
Likely Pathogenic
3
0
1
0
4
VUS
0
355
6
0
361
Likely Benign
0
5
61
109
175
Benign
0
1
5
2
8
Conflicting
—3
Total536178111558

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

View in ClinVar →

Protein Context — Lollipop Plot

HERC1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

HERC1-related macrocephaly, dysmorphic facies, and psychomotor retardation

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Macrocephaly, dysmorphic facies, and psychomotor retardation

MIM #617011

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The E3 ubiquitin ligase Herc1 modulates the response to nucleoside analogs in acute myeloid leukemia.
Jankovic M et al.·Blood Adv
2024
The HERC proteins and the nervous system.
Pérez-Villegas EM et al.·Semin Cell Dev Biol
2022Review
A new homozygous HERC1 gain-of-function variant in MDFPMR syndrome leads to mTORC1 hyperactivation and reduced autophagy during cell catabolism.
Schwarz JM et al.·Mol Genet Metab
2020
Clinical-Genetic Approach to Conditions with Macrocephaly and ASD/Behaviour Abnormalities: Variants in PTEN and PPP2R5D Are the Most Recurrent Gene Mutations in a Patient-Oriented Diagnostic Strategy.
L'Erario FF et al.·Genes (Basel)
2025
Familial Multiple Myeloma: Insights From Epidemiology and Underlying Germline Genetic Predisposition to the Clinic.
Akkus E et al.·Clin Lymphoma Myeloma Leuk
2025Review
HERC1 mutations in idiopathic intellectual disability.
Utine GE et al.·Eur J Med Genet
2017Case report
A nonsense variant in HERC1 is associated with intellectual disability, megalencephaly, thick corpus callosum and cerebellar atrophy.
Nguyen LS et al.·Eur J Hum Genet
2016Case report
Clinical features of UK Biobank subjects carrying protein-truncating variants in genes implicated in schizophrenia pathogenesis.
Curtis D·Psychiatr Genet
2022
Biallelic HERC1 mutations in a syndromic form of overgrowth and intellectual disability.
Ortega-Recalde O et al.·Clin Genet
2015Case report
Whole-genome sequencing analysis in families with recurrent pregnancy loss: A pilot study.
Workalemahu T et al.·PLoS One
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools