Is ERCC2 p.Ala635Val (c.1904C>T) pathogenic?

ERCC2 p.Ala635Val (c.1904C>T) is classified Conflicting classifications of pathogenicity in ERCC2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-02-04). AlphaMissense: likely pathogenic (0.7651); Rare (popmax 0.292%, amr); Associated with cerebrooculofacioskeletal syndrome 2.

What condition is associated with ERCC2 p.Ala635Val (c.1904C>T)?

ERCC2 p.Ala635Val (c.1904C>T) is associated with cerebrooculofacioskeletal syndrome 2, xeroderma pigmentosum group D, trichothiodystrophy 1, photosensitive (ClinVar).

How common is ERCC2 p.Ala635Val (c.1904C>T) in the general population?

ERCC2 p.Ala635Val (c.1904C>T) is rare (popmax 0.292%, amr) (gnomAD).

What do computational predictors say about ERCC2 p.Ala635Val (c.1904C>T)?

AlphaMissense predicts likely pathogenic (score 0.7651) — an in-silico prediction, not a clinical call.

ERCC2 p.Ala635Val

c.1904C>T · rs34517175 · VCV134100

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.7651 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.292%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebrooculofacioskeletal syndrome 2

Computational evidence

Protein change
AlphaMissense	0.7651	likely pathogenic
REVEL	0.815	moderately pathogenic-leaning
SaProt	LLR -10.93	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 9.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	27.3	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 0.292% Admixed American · 175/60,004 alleles

Filtering AF 0.256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.243%

Overall 0.0626% 1,010/1,613,814 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.99%	50
Admixed Americangrpmax	0.292%	343
Remaining individualsnot grpmax-eligible	0.174%	573
Middle Eastern	0.0164%	6,084
European (non-Finnish)	0.0107%	9,365
African / African-American	0.00801%	12,488
South Asian	0.00329%	30,363

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala635Val
Coding: c.1904C>T
MANE Select: NM_000400
dbSNP: rs34517175
Type: single nucleotide variant
Location: chr19:45352648 (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 635: an α-helix; the 'mediates interaction with mms19' region

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

Disease context

cerebrooculofacioskeletal syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: xeroderma pigmentosum group D trichothiodystrophy 1, photosensitive xeroderma pigmentosum

Similar variants

ERCC2 p.Ala635= Likely benign ★★ same residue
ERCC2 c.1238-1G>C Likely pathogenic ★★ same condition
ERCC2 c.1308-2A>G Likely pathogenic ★★ same condition
ERCC2 c.1378-1G>T Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1479+2T>C Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1480-1G>C Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1480-2A>C Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1544-1G>T 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-ala635val (accessed [today's date]).

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