Is ERCC2 p.Ser462Ala (c.1384T>G) pathogenic?

ERCC2 p.Ser462Ala (c.1384T>G) is classified Uncertain significance in ERCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-12). AlphaMissense: likely pathogenic (0.6421); Very rare (popmax 8.48e-05%, nfe).

How common is ERCC2 p.Ser462Ala (c.1384T>G) in the general population?

ERCC2 p.Ser462Ala (c.1384T>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ERCC2 p.Ser462Ala (c.1384T>G)?

AlphaMissense predicts likely pathogenic (score 0.6421) — an in-silico prediction, not a clinical call.

ERCC2 p.Ser462Ala

c.1384T>G · VCV3681576

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6421 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6421	likely pathogenic
REVEL	0.643	indeterminate
SaProt	LLR -6.81	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	24.1	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 8.48e-05% European (non-Finnish) · 1/1,179,640 alleles

Overall 6.84e-05% 1/1,461,438 alleles · very rare

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.Ser462Ala
Coding: c.1384T>G
MANE Select: NM_000400
Type: single nucleotide variant
Location: chr19:45357365 (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 462: an α-helix; the 'mediates interaction with mms19' region

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

Similar variants

ERCC2 p.Ser462= Likely benign ★★ same residue
MAG p.Tyr462Ser Uncertain significance ★ ⚠ same residue
MAG p.Tyr462= 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

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-ser462ala (accessed [today's date]).

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