Is ERCC2 p.Arg730Trp (c.2188C>T) pathogenic?

ERCC2 p.Arg730Trp (c.2188C>T) is classified Uncertain significance in ERCC2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-08-25). AlphaMissense: likely benign (0.1917); Very rare (popmax 0.00223%, eas).

How common is ERCC2 p.Arg730Trp (c.2188C>T) in the general population?

ERCC2 p.Arg730Trp (c.2188C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ERCC2 p.Arg730Trp (c.2188C>T)?

AlphaMissense predicts likely benign (score 0.1917) — an in-silico prediction, not a clinical call.

ERCC2 p.Arg730Trp

c.2188C>T · rs767253793 · VCV2430763

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1917 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1917	likely benign
REVEL	0.658	pathogenic-leaning
SaProt	LLR -11.30	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 0.44, 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 0.00223% East Asian · 1/44,886 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00105% 17/1,613,522 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,886
South Asian	0.0022%	45,527
Finnishnot grpmax-eligible	0.00157%	63,888
European (non-Finnish)	0.0011%	90,765

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.Arg730Trp
Coding: c.2188C>T
MANE Select: NM_000400
dbSNP: rs767253793
Type: single nucleotide variant
Location: chr19:45352211 (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 730: a UniProt-annotated variant site (in xp-d and ttd1; no longer interacts with gtf2h2/p44; has 5'-3' helicase activity)

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

Similar variants

ERCC2 p.Arg730Gln Uncertain significance ★★ ⚠ same residue
ERCC2 p.Arg730Leu Uncertain significance ★ ⚠ same residue
ERCC2 p.Arg730Pro Uncertain significance ★ ⚠ same residue
ERCC2 p.Arg730= Likely benign ★ same residue
ERCC2 c.1238-1G>C Likely pathogenic ★★ same type
ERCC2 c.1308-2A>G Likely pathogenic ★★ same type
ERCC2 c.1378-1G>T Pathogenic/Likely pathogenic ★★ same type
ERCC2 c.1479+2T>C Pathogenic/Likely 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/ercc2-p-arg730trp (accessed [today's date]).

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