Is ERCC3 p.Val405Ile (c.1213G>A) pathogenic?

ERCC3 p.Val405Ile (c.1213G>A) is classified Likely benign in ERCC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-18). AlphaMissense: likely benign (0.0627); Very rare (popmax 0.00667%, afr); Associated with Inborn genetic diseases.

What condition is associated with ERCC3 p.Val405Ile (c.1213G>A)?

ERCC3 p.Val405Ile (c.1213G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ERCC3 p.Val405Ile (c.1213G>A) in the general population?

ERCC3 p.Val405Ile (c.1213G>A) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about ERCC3 p.Val405Ile (c.1213G>A)?

AlphaMissense predicts likely benign (score 0.0627) — an in-silico prediction, not a clinical call.

ERCC3 p.Val405Ile

c.1213G>A · rs373790042 · VCV2206581

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0627 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0627	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -7.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3	GERP -4.3
Regional constraint	o/e 0.84	unconstrained · MANE · 36 kb · p 4.8e-07 · regional, not allelic
Overall
CADD	0.483	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 0.00667% African / African-American · 5/74,922 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00161% 26/1,614,082 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,984
Remaining individualsnot grpmax-eligible	0.0048%	20,829
Admixed American	0.00333%	30,003
South Asian	0.0022%	45,546
European (non-Finnish)	0.00119%	84,288

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.Val405Ile
Coding: c.1213G>A
MANE Select: NM_000122
dbSNP: rs373790042
Type: single nucleotide variant
Location: chr2:127286832 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.34 · 56 PDB
Residue 405: the helicase atp-binding domain; a β-strand

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-val405ile (accessed [today's date]).

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