Is ERCC2 p.Arg335Gln (c.1004G>A) pathogenic?

ERCC2 p.Arg335Gln (c.1004G>A) is classified Uncertain significance in ERCC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-23). AlphaMissense: ambiguous (0.5403); Very rare (popmax 0.00478%, eas); Associated with Inborn genetic diseases.

What condition is associated with ERCC2 p.Arg335Gln (c.1004G>A)?

ERCC2 p.Arg335Gln (c.1004G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ERCC2 p.Arg335Gln (c.1004G>A) in the general population?

ERCC2 p.Arg335Gln (c.1004G>A) is very rare (popmax 0.00478%, eas) (gnomAD).

What do computational predictors say about ERCC2 p.Arg335Gln (c.1004G>A)?

AlphaMissense predicts ambiguous (score 0.5403) — an in-silico prediction, not a clinical call.

ERCC2 p.Arg335Gln

c.1004G>A · rs1324891873 · VCV1778790

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5403 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00478%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5403	ambiguous
REVEL	0.628	indeterminate
SaProt	LLR -10.69	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 0.64, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	31.0	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 0.00478% East Asian · 2/41,806 alleles

Filtering AF 0.000793% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000297%

Overall 0.000214% 3/1,398,710 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00478%	20,903
Admixed American	0.00188%	53,128

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.Arg335Gln
Coding: c.1004G>A
MANE Select: NM_000400
dbSNP: rs1324891873
Type: single nucleotide variant
Location: chr19:45363857 (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 335: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ERCC2 p.Ala725Pro Pathogenic/Likely pathogenic ★★ same condition
ERCC2 p.Arg616Pro Pathogenic ★★ same condition
ERCC2 p.Ala108Thr Uncertain significance ★★ ⚠ same condition
ERCC2 p.Ala144Val Uncertain significance ★★ ⚠ same condition
ERCC2 p.Ala226Thr Uncertain significance ★★ ⚠ same condition
ERCC2 p.Ala306Val Uncertain significance ★★ ⚠ same condition
ERCC2 p.Ala318Gly Uncertain significance ★★ ⚠ same condition
ERCC2 p.Ala318Thr 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/ercc2-p-arg335gln (accessed [today's date]).

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