Is ERCC2 p.Val447Ile (c.1339G>A) pathogenic?

ERCC2 p.Val447Ile (c.1339G>A) is classified Conflicting classifications of pathogenicity in ERCC2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-10-01). AlphaMissense: likely benign (0.0834); Ultra-rare (popmax 0.0988%, sas); Associated with trichothiodystrophy 1, photosensitive.

What condition is associated with ERCC2 p.Val447Ile (c.1339G>A)?

ERCC2 p.Val447Ile (c.1339G>A) is associated with trichothiodystrophy 1, photosensitive, xeroderma pigmentosum group D (ClinVar).

How common is ERCC2 p.Val447Ile (c.1339G>A) in the general population?

ERCC2 p.Val447Ile (c.1339G>A) is ultra-rare (popmax 0.0988%, sas) (gnomAD).

What do computational predictors say about ERCC2 p.Val447Ile (c.1339G>A)?

AlphaMissense predicts likely benign (score 0.0834) — an in-silico prediction, not a clinical call.

ERCC2 p.Val447Ile

c.1339G>A · rs141457460 · VCV894684

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0834 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0988%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

trichothiodystrophy 1, photosensitive

Computational evidence

Protein change
AlphaMissense	0.0834	likely benign
REVEL	0.259	benign-leaning
SaProt	LLR -9.80	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 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	22.3	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 0.0988% South Asian · 90/91,086 alleles

Filtering AF 0.0823% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0761%

Overall 0.00818% 132/1,614,206 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0988%	1,012
Remaining individualsnot grpmax-eligible	0.0176%	5,683
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.00237%	42,144
East Asian	0.00223%	44,884
African / African-American	0.00133%	75,050

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: ERCC2
Protein: p.Val447Ile
Coding: c.1339G>A
MANE Select: NM_000400
dbSNP: rs141457460
Type: single nucleotide variant
Location: chr19:45357512 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.74 · 55 PDB
Residue 447: an α-helix; the 'mediates interaction with mms19' region

Full ERCC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

trichothiodystrophy 1, photosensitive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: xeroderma pigmentosum group D

Similar variants

ERCC2 p.Val447= Likely benign ★★ same residue
ERCC2 p.Val447Ala Uncertain significance ★ ⚠ same residue
ERCC2 p.Val447Gly Uncertain significance ★ ⚠ same residue
ERCC2 c.1308-2A>G Likely pathogenic ★★ same condition
ERCC2 c.1480-2A>C Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1666-2A>T Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1759-2A>G Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.183+2T>A Pathogenic/Likely pathogenic ★★ 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/ercc2-p-val447ile (accessed [today's date]).

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