Is ERCC2 p.Val231Met (c.691G>A) pathogenic?

ERCC2 p.Val231Met (c.691G>A) is classified Uncertain significance in ERCC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-01). AlphaMissense: likely pathogenic (0.8933); Ultra-rare (popmax 0.0981%, eas); Associated with xeroderma pigmentosum group D.

What condition is associated with ERCC2 p.Val231Met (c.691G>A)?

ERCC2 p.Val231Met (c.691G>A) is associated with xeroderma pigmentosum group D (ClinVar).

How common is ERCC2 p.Val231Met (c.691G>A) in the general population?

ERCC2 p.Val231Met (c.691G>A) is ultra-rare (popmax 0.0981%, eas) (gnomAD).

What do computational predictors say about ERCC2 p.Val231Met (c.691G>A)?

AlphaMissense predicts likely pathogenic (score 0.8933) — an in-silico prediction, not a clinical call.

ERCC2 p.Val231Met

Q: How is Xeroderma pigmentosum-Cockayne syndrome complex inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.691G>A · rs200895828 · VCV329526

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8933 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0981%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xeroderma pigmentosum group D

Computational evidence

Protein change
AlphaMissense	0.8933	likely pathogenic
REVEL	0.695	pathogenic-leaning
SaProt	LLR -13.90	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0981% East Asian · 44/44,864 alleles

Filtering AF 0.075% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0669%

Overall 0.00508% 82/1,613,978 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0981%	1,020
Middle Eastern	0.033%	3,026
Remaining individualsnot grpmax-eligible	0.0064%	15,627
South Asian	0.00549%	18,216
European (non-Finnish)	0.0022%	45,385
African / African-American	0.00133%	75,028

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.Val231Met
Coding: c.691G>A
MANE Select: NM_000400
dbSNP: rs200895828
Type: single nucleotide variant
Location: chr19:45364451 (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 231: the helicase atp-binding domain; a β-strand

Full ERCC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

xeroderma pigmentosum group D — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Xeroderma pigmentosum-Cockayne syndrome complex (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

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
ERCC2 c.183+2T>A Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.361-1G>A Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.816-2A>G Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Ala717Gly 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-val231met (accessed [today's date]).

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