Is ERCC3 p.Arg765Trp (c.2293C>T) pathogenic?

ERCC3 p.Arg765Trp (c.2293C>T) is classified Uncertain significance in ERCC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-01). AlphaMissense: likely benign (0.331); Very rare (popmax 0.00223%, eas).

How common is ERCC3 p.Arg765Trp (c.2293C>T) in the general population?

ERCC3 p.Arg765Trp (c.2293C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ERCC3 p.Arg765Trp (c.2293C>T)?

AlphaMissense predicts likely benign (score 0.331) — an in-silico prediction, not a clinical call.

ERCC3 p.Arg765Trp

c.2293C>T · rs774571443 · VCV1428473

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.331 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.331	likely benign
REVEL	0.213	benign-leaning
SaProt	LLR -11.39	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.2, phastCons 0.99
Regional constraint	o/e 0.84	unconstrained · MANE · 36 kb · p 4.8e-07 · regional, not allelic
Overall
CADD	25.9	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 · 1/44,890 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.0013% 21/1,614,028 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,890
South Asian	0.0022%	45,544
European (non-Finnish)	0.00144%	69,414
African / African-American	0.00133%	74,912

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.Arg765Trp
Coding: c.2293C>T
MANE Select: NM_000122
dbSNP: rs774571443
Type: single nucleotide variant
Location: chr2:127257652 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.34 · 56 PDB

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

Similar variants

ERCC3 p.Arg765Gln Uncertain significance ★ ⚠ same residue
ERCC3 p.Arg765= 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

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-arg765trp (accessed [today's date]).

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