Is ERCC3 p.Gln635Arg (c.1904A>G) pathogenic?

ERCC3 p.Gln635Arg (c.1904A>G) is classified Uncertain significance in ERCC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-09). AlphaMissense: likely pathogenic (0.9981); Very rare (popmax 0.000137%); Associated with xeroderma pigmentosum.

What condition is associated with ERCC3 p.Gln635Arg (c.1904A>G)?

ERCC3 p.Gln635Arg (c.1904A>G) is associated with xeroderma pigmentosum (ClinVar).

How common is ERCC3 p.Gln635Arg (c.1904A>G) in the general population?

ERCC3 p.Gln635Arg (c.1904A>G) is very rare (popmax 0.000137%) (gnomAD).

How is Xeroderma pigmentosum inherited?

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

What do computational predictors say about ERCC3 p.Gln635Arg (c.1904A>G)?

AlphaMissense predicts likely pathogenic (score 0.9981) — an in-silico prediction, not a clinical call.

ERCC3 p.Gln635Arg

c.1904A>G · rs1460478816 · VCV1692162

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9981 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000137%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xeroderma pigmentosum

Computational evidence

Protein change
AlphaMissense	0.9981	likely pathogenic
REVEL	0.872	moderately pathogenic-leaning
SaProt	LLR -15.71	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 7.8	GERP 2.3, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 36 kb · p 4.8e-07 · regional, not allelic
Overall
CADD	28.9	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 0.000137%

Overall 0.000137% 2/1,461,868 alleles · very rare

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.Gln635Arg
Coding: c.1904A>G
MANE Select: NM_000122
dbSNP: rs1460478816
Type: single nucleotide variant
Location: chr2:127271377 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.34 · 56 PDB
Residue 635: the helicase c-terminal domain; an α-helix

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

Disease context

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

For Xeroderma pigmentosum (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

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.Glu434Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC3 p.Glu105Gly Uncertain significance ★★ ⚠ same condition
ERCC3 p.Glu48Asp Uncertain significance ★★ ⚠ same condition
ERCC3 p.Glu48Gly Uncertain significance ★★ ⚠ 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-gln635arg (accessed [today's date]).

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