Is ERCC3 p.Ile401Val (c.1201A>G) pathogenic?

ERCC3 p.Ile401Val (c.1201A>G) is classified Uncertain significance in ERCC3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-04). AlphaMissense: likely benign (0.0773); Ultra-rare (popmax 0.0495%, mid).

How common is ERCC3 p.Ile401Val (c.1201A>G) in the general population?

ERCC3 p.Ile401Val (c.1201A>G) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about ERCC3 p.Ile401Val (c.1201A>G)?

AlphaMissense predicts likely benign (score 0.0773) — an in-silico prediction, not a clinical call.

ERCC3 p.Ile401Val

c.1201A>G · rs115176021 · VCV1446551

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0773 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0773	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -6.57	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 6.1	GERP 1.1, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 36 kb · p 4.8e-07 · regional, not allelic
Overall
CADD	20.9	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 0.0495% Middle Eastern · 3/6,062 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00718%

Overall 0.00477% 77/1,614,200 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.0128%	7,814
African / African-American	0.00933%	10,720
Admixed American	0.00666%	15,006
European (non-Finnish)	0.00466%	21,455

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.Ile401Val
Coding: c.1201A>G
MANE Select: NM_000122
dbSNP: rs115176021
Type: single nucleotide variant
Location: chr2:127286844 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.34 · 56 PDB
Residue 401: the helicase atp-binding domain; a turn

Full ERCC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERCC3 p.Ile401= Likely benign ★★ same residue
ERCC3 c.1828-1G>C Likely pathogenic ★★ same type
ERCC3 c.471+1G>A Pathogenic ★★ same type
ERCC3 c.657+1G>A Likely pathogenic ★★ same type
ERCC3 p.Arg109Ter Pathogenic/Likely pathogenic ★★ same type
ERCC3 p.Arg195Ter Pathogenic ★★ same type
ERCC3 p.Arg234Ter Pathogenic/Likely pathogenic ★★ same type
ERCC3 p.Arg425Ter Pathogenic ★★ same type

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-ile401val (accessed [today's date]).

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