HERC1

Chr 15AR

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

Also known as: MDFPMR, p532, p619

NCBI Gene: 8925 ENSG00000103657 UniProt: Q15751 OMIM: 605109

This protein functions as a guanine nucleotide exchange factor for ARF1 and Rab proteins and may act as an E3 ubiquitin ligase, playing roles in membrane trafficking and clathrin binding. Biallelic mutations cause autosomal recessive macrocephaly, dysmorphic facies, and psychomotor retardation. The gene is highly constrained against loss-of-function variants (pLI ~1.0, LOEUF 0.24), indicating that heterozygous loss-of-function variants are likely not tolerated in the general population.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gen encodes a member of the HERC protein family. This protein stimulates guanine nucleotide exchange on ARF1 and Rab proteins. This protein may be involved in membrane transport processes. [provided by RefSeq, Mar 2012]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.241 OMIM phenotype

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

53 unique Pathogenic / Likely Pathogenic· 842 VUS of 1816 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.19 (0.15–0.24)

0≤0.351.4

Missense OE?0.72 (0.69–0.75)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 46 / 245.4Missense obs/exp: 1838 / 2541.0Syn Z: -0.59

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveHERC1-related macrocephaly, dysmorphic facies, and psychomotor retardationLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.3097th %ile

GOF

0.2298th %ile

LOF

0.78top 5%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

1816 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic26

Likely Pathogenic27

VUS842

Likely Benign681

Benign182

Conflicting16

Pathogenic

Likely Pathogenic

842

VUS

681

Likely Benign

182

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	23	2	1	0	26
Likely Pathogenic	27	0	0	0	27
VUS	4	814	21	3	842
Likely Benign	0	29	292	360	681
Benign	0	9	154	19	182
Conflicting	—				16
Total	54	854	468	382	1,774

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap HERC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →