Is ERCC2 p.Val77Met (c.229G>A) pathogenic?

ERCC2 p.Val77Met (c.229G>A) is classified Uncertain significance in ERCC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-12-27). AlphaMissense: likely pathogenic (0.5642); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ERCC2 p.Val77Met (c.229G>A)?

ERCC2 p.Val77Met (c.229G>A) is associated with Inborn genetic diseases, xeroderma pigmentosum group D (ClinVar).

How common is ERCC2 p.Val77Met (c.229G>A) in the general population?

ERCC2 p.Val77Met (c.229G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ERCC2 p.Val77Met (c.229G>A)?

AlphaMissense predicts likely pathogenic (score 0.5642) — an in-silico prediction, not a clinical call.

ERCC2 p.Val77Met

c.229G>A · rs866646197 · VCV894709

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5642 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5642	likely pathogenic
REVEL	0.241	benign-leaning
SaProt	LLR -9.46	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 1,402 bp · p 2.6e-05 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,042 alleles

Overall 6.84e-05% 1/1,461,886 alleles · very rare

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: ERCC2
Protein: p.Val77Met
Coding: c.229G>A
MANE Select: NM_000400
dbSNP: rs866646197
Type: single nucleotide variant
Location: chr19:45368947 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.74 · 55 PDB
Residue 77: the helicase atp-binding domain; an α-helix

Full ERCC2 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

Also linked: xeroderma pigmentosum group D

Similar variants

ERCC2 p.Val77Leu Uncertain significance ★ ⚠ same residue
MAG p.Arg77Ser Uncertain significance ★ ⚠ same residue
MAG p.Arg77Leu Uncertain significance ★★ ⚠ same residue
MAG p.Arg77His Likely benign ★★ same residue
ERCC2 c.1308-2A>G Likely pathogenic ★★ same condition
ERCC2 c.1480-2A>C Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1666-2A>T Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1759-2A>G Pathogenic/Likely pathogenic ★★ 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/ercc2-p-val77met (accessed [today's date]).

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