Is XPC p.Ala674Val (c.2021C>T) pathogenic?

XPC p.Ala674Val (c.2021C>T) is classified Uncertain significance in XPC (ClinVar, Single submitter, 1 submitter; last evaluated 2016-06-01). AlphaMissense: ambiguous (0.4827); Very rare (popmax 0.00801%, afr).

How common is XPC p.Ala674Val (c.2021C>T) in the general population?

XPC p.Ala674Val (c.2021C>T) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about XPC p.Ala674Val (c.2021C>T)?

AlphaMissense predicts ambiguous (score 0.4827) — an in-silico prediction, not a clinical call.

XPC p.Ala674Val

c.2021C>T · rs894430246 · VCV809432

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4827 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Computational evidence

Protein change
AlphaMissense	0.4827	ambiguous
REVEL	0.354	indeterminate
SaProt	LLR -9.39	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 33 kb · p 0.33 · regional, not allelic
Overall
CADD	27.8	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 0.00801% African / African-American · 6/74,862 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.0018% 29/1,613,366 alleles · very rare exomes 19/1,461,272 · genomes 10/152,094 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,477
South Asian	0.0022%	45,505
European (non-Finnish)	0.00161%	62,089
Remaining individualsnot grpmax-eligible	0.0016%	62,444
Finnishnot grpmax-eligible	0.00156%	63,990

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: XPC
Protein: p.Ala674Val
Coding: c.2021C>T
MANE Select: NM_004628
dbSNP: rs894430246
Type: single nucleotide variant
Location: chr3:14156347 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.67 · 18 PDB
Residue 674: the 'interaction with rad23b' region; the 'minimal sensor domain involved in damage recognition' region; the 'dna-binding; preference for heteroduplex dna' region

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

Similar variants

XPC p.Ala674Ser Uncertain significance ★ ⚠ same residue
XPC p.Ala674= Likely benign ★ same residue
XPC p.Ala674fs Pathogenic/Likely pathogenic ★★ same residue
XPC c.104-2A>G Likely pathogenic ★★ same type
XPC c.1872+1G>A Likely pathogenic ★★ same type
XPC c.1872+1G>C Pathogenic/Likely pathogenic ★★ same type
XPC c.2033+1G>A Pathogenic/Likely pathogenic ★★ same type
XPC c.2251-1G>C 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/xpc-p-ala674val (accessed [today's date]).

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