Is ERCC2 p.Val476Ile (c.1426G>A) pathogenic?

ERCC2 p.Val476Ile (c.1426G>A) is classified Conflicting classifications of pathogenicity in ERCC2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-24). AlphaMissense: likely benign (0.1096); Rare (popmax 0.789%, sas); Associated with xeroderma pigmentosum group D.

What condition is associated with ERCC2 p.Val476Ile (c.1426G>A)?

ERCC2 p.Val476Ile (c.1426G>A) is associated with xeroderma pigmentosum group D, xeroderma pigmentosum (ClinVar).

How common is ERCC2 p.Val476Ile (c.1426G>A) in the general population?

ERCC2 p.Val476Ile (c.1426G>A) is rare (popmax 0.789%, sas) (gnomAD).

What do computational predictors say about ERCC2 p.Val476Ile (c.1426G>A)?

AlphaMissense predicts likely benign (score 0.1096) — an in-silico prediction, not a clinical call.

ERCC2 p.Val476Ile

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

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

c.1426G>A · rs531021258 · VCV795182

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1096 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.789%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

xeroderma pigmentosum group D

Computational evidence

Protein change
AlphaMissense	0.1096	likely benign
REVEL	0.452	indeterminate
SaProt	LLR -9.00	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.4, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	23.0	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 0.789% South Asian · 719/91,072 alleles

Filtering AF 0.742% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.723%

Overall 0.0497% 802/1,614,060 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.789%	127
Middle Eastern	0.099%	1,010
Remaining individualsnot grpmax-eligible	0.056%	1,786
East Asian	0.0134%	7,479
African / African-American	0.004%	25,013
European (non-Finnish)	0.0028%	35,756

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.Val476Ile
Coding: c.1426G>A
MANE Select: NM_000400
dbSNP: rs531021258
Type: single nucleotide variant
Location: chr19:45357323 (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 476: the 'mediates interaction with mms19' region

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

Also linked: xeroderma pigmentosum

For Xeroderma pigmentosum-Cockayne syndrome complex (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ERCC2 p.Val476Phe Uncertain significance ★ ⚠ 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
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

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-val476ile (accessed [today's date]).

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