Is HERC2 p.Ala976Val (c.2927C>T) pathogenic?

HERC2 p.Ala976Val (c.2927C>T) is classified Uncertain significance in HERC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-02). AlphaMissense: likely benign (0.088); Ultra-rare (popmax 0.0463%, sas); Associated with Inborn genetic diseases.

What condition is associated with HERC2 p.Ala976Val (c.2927C>T)?

HERC2 p.Ala976Val (c.2927C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HERC2 p.Ala976Val (c.2927C>T) in the general population?

HERC2 p.Ala976Val (c.2927C>T) is ultra-rare (popmax 0.0463%, sas) (gnomAD).

What do computational predictors say about HERC2 p.Ala976Val (c.2927C>T)?

AlphaMissense predicts likely benign (score 0.088) — an in-silico prediction, not a clinical call.

HERC2 p.Ala976Val

c.2927C>T · rs754896051 · VCV3105378

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.088 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0463%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.088	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 32 kb · p 9.2e-24 · regional, not allelic
Overall
CADD	15.67	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0463% South Asian · 41/88,502 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0311%

Overall 0.00362% 58/1,603,488 alleles · ultra-rare exomes 54/1,451,342 · genomes 4/152,146 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0463%	2,159
Remaining individualsnot grpmax-eligible	0.00483%	20,707
Admixed American	0.00175%	57,230
European (non-Finnish)	0.0011%	90,507

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: HERC2
Protein: p.Ala976Val
Coding: c.2927C>T
MANE Select: NM_004667
dbSNP: rs754896051
Type: single nucleotide variant
Location: chr15:28254463 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)

Full HERC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HERC2 p.Ala976Thr Uncertain significance ★ ⚠ same residue
HERC2 p.Ala976= Likely benign ★ same residue
HERC2 p.Ala1253Thr Uncertain significance ★★ same condition
HERC2 p.Ala1454Thr Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala200Val Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala2331Val Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala2458Thr Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala2671Gly Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/herc2-p-ala976val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown