Is ERCC3 p.Val471Ile (c.1411G>A) pathogenic?

ERCC3 p.Val471Ile (c.1411G>A) is classified Uncertain significance in ERCC3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-06). AlphaMissense: likely pathogenic (0.6334); Rare (popmax 0.131%, eas); Associated with xeroderma pigmentosum group B.

What condition is associated with ERCC3 p.Val471Ile (c.1411G>A)?

ERCC3 p.Val471Ile (c.1411G>A) is associated with xeroderma pigmentosum group B, trichothiodystrophy 2, photosensitive (ClinVar).

How common is ERCC3 p.Val471Ile (c.1411G>A) in the general population?

ERCC3 p.Val471Ile (c.1411G>A) is rare (popmax 0.131%, eas) (gnomAD).

What do computational predictors say about ERCC3 p.Val471Ile (c.1411G>A)?

AlphaMissense predicts likely pathogenic (score 0.6334) — an in-silico prediction, not a clinical call.

ERCC3 p.Val471Ile

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

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

c.1411G>A · rs371627165 · VCV894782

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6334 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.131%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xeroderma pigmentosum group B

Computational evidence

Protein change
AlphaMissense	0.6334	likely pathogenic
REVEL	0.238	benign-leaning
SaProt	LLR -9.90	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 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 36 kb · p 4.8e-07 · regional, not allelic
Overall
CADD	27.2	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 0.131% East Asian · 59/44,896 alleles

Filtering AF 0.105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0949%

Overall 0.0149% 241/1,614,202 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.131%	761
South Asian	0.0703%	1,423
Remaining individualsnot grpmax-eligible	0.0432%	2,315
African / African-American	0.0187%	5,362
European (non-Finnish)	0.00644%	15,527
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

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: ERCC3
Protein: p.Val471Ile
Coding: c.1411G>A
MANE Select: NM_000122
dbSNP: rs371627165
Type: single nucleotide variant
Location: chr2:127280563 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.34 · 56 PDB
Residue 471: the helicase atp-binding domain

Full ERCC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: trichothiodystrophy 2, photosensitive

For Xeroderma pigmentosum-Cockayne syndrome complex (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ERCC3 c.1828-1G>C Likely pathogenic ★★ same condition
ERCC3 c.471+1G>A Pathogenic ★★ same condition
ERCC3 c.657+1G>A Likely pathogenic ★★ same condition
ERCC3 p.Arg109Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC3 p.Arg195Ter Pathogenic ★★ same condition
ERCC3 p.Arg425Ter Pathogenic ★★ same condition
ERCC3 p.Arg452Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC3 p.Arg530Ter 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/ercc3-p-val471ile (accessed [today's date]).

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