Is ERCC3 p.Thr232Ala (c.694A>G) pathogenic?

ERCC3 p.Thr232Ala (c.694A>G) is classified Uncertain significance in ERCC3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-12-03). AlphaMissense: likely benign (0.0679); Ultra-rare (popmax 0.026%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ERCC3 p.Thr232Ala (c.694A>G)?

ERCC3 p.Thr232Ala (c.694A>G) is associated with Inborn genetic diseases, xeroderma pigmentosum (ClinVar).

How common is ERCC3 p.Thr232Ala (c.694A>G) in the general population?

ERCC3 p.Thr232Ala (c.694A>G) is ultra-rare (popmax 0.026%, nfe) (gnomAD).

What do computational predictors say about ERCC3 p.Thr232Ala (c.694A>G)?

AlphaMissense predicts likely benign (score 0.0679) — an in-silico prediction, not a clinical call.

ERCC3 p.Thr232Ala

c.694A>G · rs201383161 · VCV1352226

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0679 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.026%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0679	likely benign
REVEL	0.291	indeterminate
SaProt	LLR -7.87	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 2.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 36 kb · p 4.8e-07 · regional, not allelic
Overall
CADD	18.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.026% European (non-Finnish) · 307/1,180,014 alleles

Filtering AF 0.0236% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0227%

Overall 0.0198% 319/1,612,718 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.026%	3,844
Remaining individualsnot grpmax-eligible	0.00962%	10,393
African / African-American	0.00534%	18,716
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Finnishnot grpmax-eligible	0.00156%	64,038

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.Thr232Ala
Coding: c.694A>G
MANE Select: NM_000122
dbSNP: rs201383161
Type: single nucleotide variant
Location: chr2:127289465 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.34 · 56 PDB
Residue 232: the 'disordered' region

Full ERCC3 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

Also linked: xeroderma pigmentosum

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.Gln711Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC3 p.Glu434Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC3 p.Ala120Val Uncertain significance ★★ ⚠ same condition
ERCC3 p.Arg109Gln 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-thr232ala (accessed [today's date]).

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