Is ERCC2 p.Arg450Cys (c.1348C>T) pathogenic?

ERCC2 p.Arg450Cys (c.1348C>T) is classified Uncertain significance in ERCC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-26). AlphaMissense: ambiguous (0.5386); Very rare (popmax 0.00267%, afr).

How common is ERCC2 p.Arg450Cys (c.1348C>T) in the general population?

ERCC2 p.Arg450Cys (c.1348C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ERCC2 p.Arg450Cys (c.1348C>T)?

AlphaMissense predicts ambiguous (score 0.5386) — an in-silico prediction, not a clinical call.

ERCC2 p.Arg450Cys

c.1348C>T · rs749815182 · VCV2503916

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5386 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5386	ambiguous
REVEL	0.661	pathogenic-leaning
SaProt	LLR -15.28	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 0.5, 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 0.00267% African / African-American · 2/74,926 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000929% 15/1,614,040 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,463
East Asian	0.00223%	44,896
European (non-Finnish)	0.00102%	98,332

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.Arg450Cys
Coding: c.1348C>T
MANE Select: NM_000400
dbSNP: rs749815182
Type: single nucleotide variant
Location: chr19:45357503 (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 450: 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.Arg450His Uncertain significance ★★ ⚠ same residue
ERCC2 p.Arg450= 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

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-arg450cys (accessed [today's date]).

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