Is ERCC3 p.Gln433Glu (c.1297C>G) pathogenic?

ERCC3 p.Gln433Glu (c.1297C>G) is classified Uncertain significance in ERCC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-09). AlphaMissense: ambiguous (0.3923); Absent from gnomAD v4.1; Associated with xeroderma pigmentosum.

What condition is associated with ERCC3 p.Gln433Glu (c.1297C>G)?

ERCC3 p.Gln433Glu (c.1297C>G) is associated with xeroderma pigmentosum (ClinVar).

How common is ERCC3 p.Gln433Glu (c.1297C>G) in the general population?

ERCC3 p.Gln433Glu (c.1297C>G) is absent from gnomAD v4.1 (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.Gln433Glu (c.1297C>G)?

AlphaMissense predicts ambiguous (score 0.3923) — an in-silico prediction, not a clinical call.

ERCC3 p.Gln433Glu

c.1297C>G · rs766583866 · VCV1692157

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3923 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

xeroderma pigmentosum

Computational evidence

Protein change
AlphaMissense	0.3923	ambiguous
REVEL	0.281	benign-leaning
SaProt	LLR -11.25	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 36 kb · p 4.8e-07 · regional, not allelic
Overall
CADD	24.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ERCC3
Protein: p.Gln433Glu
Coding: c.1297C>G
MANE Select: NM_000122
dbSNP: rs766583866
Type: single nucleotide variant
Location: chr2:127286748 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.34 · 56 PDB
Residue 433: the helicase atp-binding domain

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 p.Gln433= Likely benign ★ same residue
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

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-gln433glu (accessed [today's date]).

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