Is ERCC2 p.Arg227Cys (c.679C>T) pathogenic?

ERCC2 p.Arg227Cys (c.679C>T) is classified Uncertain significance in ERCC2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-01-06). AlphaMissense: likely benign (0.2212); Rare (popmax 0.115%, mid); Associated with trichothiodystrophy 1, photosensitive.

What condition is associated with ERCC2 p.Arg227Cys (c.679C>T)?

ERCC2 p.Arg227Cys (c.679C>T) is associated with trichothiodystrophy 1, photosensitive, cerebrooculofacioskeletal syndrome 2 (ClinVar).

How common is ERCC2 p.Arg227Cys (c.679C>T) in the general population?

ERCC2 p.Arg227Cys (c.679C>T) is rare (popmax 0.115%, mid) (gnomAD).

What do computational predictors say about ERCC2 p.Arg227Cys (c.679C>T)?

AlphaMissense predicts likely benign (score 0.2212) — an in-silico prediction, not a clinical call.

ERCC2 p.Arg227Cys

c.679C>T · rs137910235 · VCV134116

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2212 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.115%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

trichothiodystrophy 1, photosensitive

Computational evidence

Protein change
AlphaMissense	0.2212	likely benign
REVEL	0.379	indeterminate
SaProt	LLR -11.58	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	33.0	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 0.115% Middle Eastern · 7/6,068 alleles

Filtering AF 0.0794% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0728%

Overall 0.0117% 189/1,613,902 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.115%	867
African / African-American	0.0974%	1,026
European (non-Finnish)	0.00856%	11,683
Remaining individualsnot grpmax-eligible	0.008%	12,497
Admixed American	0.005%	19,999

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.Arg227Cys
Coding: c.679C>T
MANE Select: NM_000400
dbSNP: rs137910235
Type: single nucleotide variant
Location: chr19:45364463 (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 227: the helicase atp-binding domain

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: cerebrooculofacioskeletal syndrome 2

Similar variants

ERCC2 p.Arg227Gly Uncertain significance ★ ⚠ same residue
ERCC2 p.Arg227His Uncertain significance ★ ⚠ same residue
ERCC2 p.Arg227Leu Uncertain significance ★ same residue
MAG p.Gln227= Likely benign ★ same residue
ERCC2 c.1238-1G>C Likely pathogenic ★★ same condition
ERCC2 c.1308-2A>G Likely pathogenic ★★ same condition
ERCC2 c.1378-1G>T Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1479+2T>C 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-arg227cys (accessed [today's date]).

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