Is ERCC2 p.Thr653Ile (c.1958C>T) pathogenic?

ERCC2 p.Thr653Ile (c.1958C>T) is classified Uncertain significance in ERCC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-08-13). AlphaMissense: likely pathogenic (0.9534); Ultra-rare (popmax 0.01%, amr); Associated with trichothiodystrophy 1, photosensitive.

What condition is associated with ERCC2 p.Thr653Ile (c.1958C>T)?

ERCC2 p.Thr653Ile (c.1958C>T) is associated with trichothiodystrophy 1, photosensitive (ClinVar).

How common is ERCC2 p.Thr653Ile (c.1958C>T) in the general population?

ERCC2 p.Thr653Ile (c.1958C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about ERCC2 p.Thr653Ile (c.1958C>T)?

AlphaMissense predicts likely pathogenic (score 0.9534) — an in-silico prediction, not a clinical call.

ERCC2 p.Thr653Ile

c.1958C>T · rs763885481 · VCV1327073

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9534 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

trichothiodystrophy 1, photosensitive

Computational evidence

Protein change
AlphaMissense	0.9534	likely pathogenic
REVEL	0.768	pathogenic-leaning
SaProt	LLR -9.98	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	27.8	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 0.01% Admixed American · 6/60,000 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000929% 15/1,613,920 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,000
South Asian	0.0022%	45,544
European (non-Finnish)	0.000593%	168,577

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.Thr653Ile
Coding: c.1958C>T
MANE Select: NM_000400
dbSNP: rs763885481
Type: single nucleotide variant
Location: chr19:45352594 (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 653: an α-helix

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

Similar variants

ERCC2 p.Thr653= Likely benign ★★ same residue
ERCC2 p.Thr653Ser 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
ERCC2 c.361-1G>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-thr653ile (accessed [today's date]).

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