Is ERCC2 p.Arg450His (c.1349G>A) pathogenic?

ERCC2 p.Arg450His (c.1349G>A) is classified Uncertain significance in ERCC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-09-20). AlphaMissense: likely benign (0.2786); Ultra-rare (popmax 0.0235%, nfe); Associated with xeroderma pigmentosum.

What condition is associated with ERCC2 p.Arg450His (c.1349G>A)?

ERCC2 p.Arg450His (c.1349G>A) is associated with xeroderma pigmentosum, xeroderma pigmentosum group D (ClinVar).

How common is ERCC2 p.Arg450His (c.1349G>A) in the general population?

ERCC2 p.Arg450His (c.1349G>A) is ultra-rare (popmax 0.0235%, nfe) (gnomAD).

How is Xeroderma pigmentosum inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ERCC2 p.Arg450His (c.1349G>A)?

AlphaMissense predicts likely benign (score 0.2786) — an in-silico prediction, not a clinical call.

ERCC2 p.Arg450His

c.1349G>A · rs146632315 · VCV894683

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2786 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0235%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

xeroderma pigmentosum

Computational evidence

Protein change
AlphaMissense	0.2786	likely benign
REVEL	0.584	indeterminate
SaProt	LLR -12.95	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 17 kb · p 0.48 · regional, not allelic
Overall
CADD	26.3	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 0.0235% European (non-Finnish) · 277/1,179,994 alleles

Filtering AF 0.0212% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0203%

Overall 0.0185% 298/1,614,006 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0235%	4,260
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0112%	8,926
Finnishnot grpmax-eligible	0.0109%	9,146
South Asian	0.00329%	30,361
African / African-American	0.00267%	37,460
Admixed American	0.00167%	60,002

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.Arg450His
Coding: c.1349G>A
MANE Select: NM_000400
dbSNP: rs146632315
Type: single nucleotide variant
Location: chr19:45357502 (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

Disease context

xeroderma pigmentosum — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: xeroderma pigmentosum group D

For Xeroderma pigmentosum (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

ERCC2 p.Arg450= Likely benign ★★ same residue
ERCC2 p.Arg450Cys Uncertain significance ★ ⚠ same residue
ERCC2 c.1308-2A>G Likely pathogenic ★★ same condition
ERCC2 c.1480-2A>C Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1666-2A>T Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.1759-2A>G Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.183+2T>A Pathogenic/Likely pathogenic ★★ same condition
ERCC2 c.361-1G>A Pathogenic/Likely pathogenic ★★ same condition

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-arg450his (accessed [today's date]).

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