HERC2

Chr 15AR

HECT and RLD domain containing E3 ubiquitin protein ligase 2

Also known as: D15F37S1, MRT38, SHEP1, jdf2, p528

NCBI Gene: 8924ENSG00000128731UniProt: O95714

This gene belongs to the HERC gene family that encodes a group of unusually large proteins, which contain multiple structural domains. All members have at least 1 copy of an N-terminal region showing homology to the cell cycle regulator RCC1 and a C-terminal HECT (homologous to E6-AP C terminus) domain found in a number of E3 ubiquitin protein ligases. Genetic variations in this gene are associated with skin/hair/eye pigmentation variability. Multiple pseudogenes of this gene are located on chromosomes 15 and 16. [provided by RefSeq, Mar 2012]

Primary Disease Associations & Inheritance

[Skin/hair/eye pigmentation 1, blond/brown hair]MIM #227220
AR
[Skin/hair/eye pigmentation 1, blue/nonblue eyes]MIM #227220
AR
Intellectual developmental disorder, autosomal recessive 38MIM #615516
AR
579
ClinVar variants
30
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— HERC2
⚡
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
30 Pathogenic / Likely Pathogenic· 394 VUS of 579 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.
0.20LOEUF
pLI 1.000
Z-score 12.07
OE 0.15 (0.12–0.20)
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.
4.42Z-score
OE missense 0.76 (0.73–0.79)
2105 obs / 2758.9 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.0.15 (0.12–0.20)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.76 (0.73–0.79)
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.1.09
0≤1.21.6
LoF obs/exp: 36 / 236.3Missense obs/exp: 2105 / 2758.9Syn Z: -2.51

ClinVar Variant Classifications

579 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23
Likely Pathogenic7
VUS394
Likely Benign141
Benign8
Conflicting6
23
Pathogenic
7
Likely Pathogenic
394
VUS
141
Likely Benign
8
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
22
0
23
Likely Pathogenic
3
1
3
0
7
VUS
1
380
11
2
394
Likely Benign
0
8
13
120
141
Benign
0
1
2
5
8
Conflicting
—6
Total539051127579

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

View in ClinVar →

Protein Context — Lollipop Plot

HERC2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

HERC2-related neurodevelopmental disorder

strong
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

[Skin/hair/eye pigmentation 1, blond/brown hair]

MIM #227220

Molecular basis of disorder known

Autosomal recessive

[Skin/hair/eye pigmentation 1, blue/nonblue eyes]

MIM #227220

Molecular basis of disorder known

Autosomal recessive

Intellectual developmental disorder, autosomal recessive 38

MIM #615516

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — HERC2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Cryptochrome 1 regulates ovarian granulosa cell senescence through NCOA4-mediated ferritinophagy.
Ma J et al.·Free Radic Biol Med
2024
Mycobacterium tuberculosis hijacks host TRIM21- and NCOA4-dependent ferritinophagy to enhance intracellular growth.
Dai Y et al.·J Clin Invest
2023
The HERC proteins and the nervous system.
Pérez-Villegas EM et al.·Semin Cell Dev Biol
2022Review
Loss of MNX1 Sensitizes Tumors to Cytotoxic T Cells by Degradation of PD-L1 mRNA.
Li Z et al.·Adv Sci (Weinh)
2025
HERC2 deficiency activates C-RAF/MKK3/p38 signalling pathway altering the cellular response to oxidative stress.
Sala-Gaston J et al.·Cell Mol Life Sci
2022
Genomic variant profiling in blast-phase paediatric chronic myeloid leukaemia: Predisposing and driving alterations.
Behrens YL et al.·Br J Haematol
2025
Genotype-phenotype associations and human eye color.
White D et al.·J Hum Genet
2011Review
Interactions between HERC2, OCA2 and MC1R may influence human pigmentation phenotype.
Branicki W et al.·Ann Hum Genet
2009
Delineating the expanding phenotype of HERC2-related disorders: The impact of biallelic loss of function versus missense variation.
Vincent KM et al.·Clin Genet
2021
Immune Cell Landscape in Gastric Cancer.
Yang Y et al.·Biomed Res Int
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
SV2B Promotes the Progression of TFE3-Rearranged Renal Cell Carcinoma by Interacting with HERC2 to Impede the Degradation of NF-κB Subunits.
Feng H et al.·Adv Sci (Weinh)
2026🔓 Open Access
HERC2 as a Potential Biomarker for Prognosis and Response to Bevacizumab in Ovarian Cancer: A Bioinformatics Approach.
Yay F et al.·Reprod Sci
2025
Nephroprotective mechanism of Kunkui Baoshen decoction in diabetic kidney disease: Targeting the HERC2/NCOA4-mediated autophagy-dependent ferroptosis pathway.
Song SY et al.·World J Diabetes
2025🔓 Open AccessFunctional
Cigarette smoke disrupts osteogenic-adipogenic balance via Nrf2/HERC2 axis-driven ferroptosis.
Li W et al.·Free Radic Biol Med
2025
Mechanistic insights into the iron-sulfur cluster-dependent interaction of the autophagy receptor NCOA4 with the E3 ligase HERC2.
Liu H et al.·Proc Natl Acad Sci U S A
2025🔓 Open Access
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