Is ERCC2 p.Val611Ala (c.1832T>C) pathogenic?

ERCC2 p.Val611Ala (c.1832T>C) is classified Uncertain significance in ERCC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2021-11-03). AlphaMissense: ambiguous (0.4164); Very rare (popmax 0.00322%, nfe); Associated with trichothiodystrophy 1, photosensitive.

What condition is associated with ERCC2 p.Val611Ala (c.1832T>C)?

ERCC2 p.Val611Ala (c.1832T>C) is associated with trichothiodystrophy 1, photosensitive, xeroderma pigmentosum group D (ClinVar).

How common is ERCC2 p.Val611Ala (c.1832T>C) in the general population?

ERCC2 p.Val611Ala (c.1832T>C) is very rare (popmax 0.00322%, nfe) (gnomAD).

What do computational predictors say about ERCC2 p.Val611Ala (c.1832T>C)?

AlphaMissense predicts ambiguous (score 0.4164) — an in-silico prediction, not a clinical call.

ERCC2 p.Val611Ala

c.1832T>C · rs759116129 · VCV893461

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4164 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00322%, nfe)

Conditions

trichothiodystrophy 1, photosensitive

Computational evidence

Protein change
AlphaMissense	0.4164	ambiguous
REVEL	0.561	indeterminate
SaProt	LLR -2.66	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	22.6	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 0.00322% European (non-Finnish) · 38/1,179,764 alleles

Filtering AF 0.00239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.0026% 42/1,613,326 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00322%	31,046
Remaining individualsnot grpmax-eligible	0.0032%	31,227
African / African-American	0.00134%	74,762
South Asian	0.0011%	91,078

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.Val611Ala
Coding: c.1832T>C
MANE Select: NM_000400
dbSNP: rs759116129
Type: single nucleotide variant
Location: chr19:45352816 (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 611: the 'mediates interaction with mms19' region

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

Disease context

trichothiodystrophy 1, photosensitive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: xeroderma pigmentosum group D

Similar variants

MAG p.Tyr611Cys Uncertain significance ★ ⚠ same residue
MAG p.Tyr611His Uncertain significance ★ ⚠ same residue
ERCC2 p.Val611= 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
ERCC2 c.183+2T>A 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-val611ala (accessed [today's date]).

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