Is ERCC3 p.Val565Ala (c.1694T>C) pathogenic?

ERCC3 p.Val565Ala (c.1694T>C) is classified Uncertain significance in ERCC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-04). AlphaMissense: likely pathogenic (0.9932); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ERCC3 p.Val565Ala (c.1694T>C)?

ERCC3 p.Val565Ala (c.1694T>C) is associated with Inborn genetic diseases (ClinVar).

How common is ERCC3 p.Val565Ala (c.1694T>C) in the general population?

ERCC3 p.Val565Ala (c.1694T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ERCC3 p.Val565Ala (c.1694T>C)?

AlphaMissense predicts likely pathogenic (score 0.9932) — an in-silico prediction, not a clinical call.

ERCC3 p.Val565Ala

c.1694T>C · rs2468040225 · VCV2543574

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9932 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9932	likely pathogenic
REVEL	0.895	moderately pathogenic-leaning
SaProt	LLR -13.60	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 11	GERP 2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 36 kb · p 4.8e-07 · regional, not allelic
Overall
CADD	28.8	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 8.48e-05% European (non-Finnish) · 1/1,179,622 alleles

Overall 6.84e-05% 1/1,461,412 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.Val565Ala
Coding: c.1694T>C
MANE Select: NM_000122
dbSNP: rs2468040225
Type: single nucleotide variant
Location: chr2:127279209 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.34 · 56 PDB
Residue 565: the helicase c-terminal domain; an α-helix

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

Similar variants

ERCC3 p.Gln711Ter Pathogenic/Likely pathogenic ★★ same condition
ERCC3 p.Ala120Val Uncertain significance ★★ ⚠ same condition
ERCC3 p.Arg109Gln Uncertain significance ★★ ⚠ same condition
ERCC3 p.Arg283His Uncertain significance ★★ ⚠ same condition
ERCC3 p.Arg334His Uncertain significance ★★ ⚠ same condition
ERCC3 p.Arg453Lys Uncertain significance ★★ ⚠ same condition
ERCC3 p.Arg634Cys Uncertain significance ★★ ⚠ same condition
ERCC3 p.Arg743Cys 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-val565ala (accessed [today's date]).

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