Is ERCC2 p.Pro355Thr (c.1063C>A) pathogenic?

ERCC2 p.Pro355Thr (c.1063C>A) is classified Uncertain significance in ERCC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0836); Absent from gnomAD v4.1.

How common is ERCC2 p.Pro355Thr (c.1063C>A) in the general population?

ERCC2 p.Pro355Thr (c.1063C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ERCC2 p.Pro355Thr (c.1063C>A)?

AlphaMissense predicts likely benign (score 0.0836) — an in-silico prediction, not a clinical call.

ERCC2 p.Pro355Thr

c.1063C>A · rs2123285561 · VCV1400626

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0836 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,539,636)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0836	likely benign
REVEL	0.225	benign-leaning
SaProt	LLR -5.23	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	17.64	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,539,636). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ERCC2
Protein: p.Pro355Thr
Coding: c.1063C>A
MANE Select: NM_000400
dbSNP: rs2123285561
Type: single nucleotide variant
Location: chr19:45363798 (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 355: an α-helix

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

Similar variants

ERCC2 p.Pro355= 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
ERCC2 c.1480-1G>C Pathogenic/Likely pathogenic ★★ same type
ERCC2 c.1480-2A>C Pathogenic/Likely pathogenic ★★ same type
ERCC2 c.1544-1G>T 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-pro355thr (accessed [today's date]).

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