Is ERCC3 p.Ser735Pro (c.2203T>C) pathogenic?

ERCC3 p.Ser735Pro (c.2203T>C) is classified Benign in ERCC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-24). AlphaMissense: likely benign (0.0932); Rare (popmax 0.455%, eas).

How common is ERCC3 p.Ser735Pro (c.2203T>C) in the general population?

ERCC3 p.Ser735Pro (c.2203T>C) is rare (popmax 0.455%, eas) (gnomAD).

What do computational predictors say about ERCC3 p.Ser735Pro (c.2203T>C)?

AlphaMissense predicts likely benign (score 0.0932) — an in-silico prediction, not a clinical call.

ERCC3 p.Ser735Pro

c.2203T>C · rs4150522 · VCV762376

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0932 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.455%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0932	likely benign
REVEL	0.446	indeterminate
SaProt	LLR -6.58	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP -0.33, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 36 kb · p 4.8e-07 · regional, not allelic
Overall
CADD	19.19	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 0.455% East Asian · 204/44,884 alleles

Filtering AF 0.403% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.384%

Overall 0.0131% 212/1,614,178 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.455%	220
Remaining individualsnot grpmax-eligible	0.0048%	20,837
South Asian	0.00439%	22,769
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

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.Ser735Pro
Coding: c.2203T>C
MANE Select: NM_000122
dbSNP: rs4150522
Type: single nucleotide variant
Location: chr2:127259310 (GRCh38)
Gene constraint: LOEUF 0.797 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.34 · 56 PDB
Residue 735: a UniProt-annotated variant site (in)

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

Similar variants

ERCC3 p.Ser735= 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
ERCC3 p.Arg425Ter 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-ser735pro (accessed [today's date]).

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