Is XPC p.Ala896Val (c.2687C>T) pathogenic?

XPC p.Ala896Val (c.2687C>T) is classified Uncertain significance in XPC (ClinVar, Single submitter, 1 submitter; last evaluated 2026-06-30). AlphaMissense: likely benign (0.1174); Very rare (popmax 0.00822%, nfe).

How common is XPC p.Ala896Val (c.2687C>T) in the general population?

XPC p.Ala896Val (c.2687C>T) is very rare (popmax 0.00822%, nfe) (gnomAD).

What do computational predictors say about XPC p.Ala896Val (c.2687C>T)?

AlphaMissense predicts likely benign (score 0.1174) — an in-silico prediction, not a clinical call.

XPC p.Ala896Val

c.2687C>T · VCV4887145

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1174 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00822%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1174	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	LLR -5.16	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 4.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 33 kb · p 0.33 · regional, not allelic
Overall
CADD	22.3	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

Grpmax group 0.00822% European (non-Finnish) · 97/1,179,440 alleles

Filtering AF 0.00689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00634%

Overall 0.00639% 103/1,612,226 alleles · very rare exomes 98/1,460,844 · genomes 5/151,382 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00822%	12,159
Remaining individualsnot grpmax-eligible	0.0032%	31,214
African / African-American	0.00268%	37,327
Finnishnot grpmax-eligible	0.00158%	63,442
South Asian	0.0011%	90,906

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.Ala896Val
Coding: c.2687C>T
MANE Select: NM_004628
Type: single nucleotide variant
Location: chr3:14146077 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.67 · 18 PDB
Residue 896: the 'disordered' region; an α-helix; the 'interaction with ercc2 and gtf2h1' region

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

Similar variants

XPC p.Ala896= Likely benign ★ 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
XPC c.2420+2T>C Pathogenic/Likely pathogenic ★★ same type
XPC c.299+1G>A 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/xpc-p-ala896val (accessed [today's date]).

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