Is XPC p.Ile232Val (c.694A>G) pathogenic?

XPC p.Ile232Val (c.694A>G) is classified Uncertain significance in XPC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-08). AlphaMissense: likely benign (0.0749); Ultra-rare (popmax 0.0496%, mid).

How common is XPC p.Ile232Val (c.694A>G) in the general population?

XPC p.Ile232Val (c.694A>G) is ultra-rare (popmax 0.0496%, mid) (gnomAD).

What do computational predictors say about XPC p.Ile232Val (c.694A>G)?

AlphaMissense predicts likely benign (score 0.0749) — an in-silico prediction, not a clinical call.

XPC p.Ile232Val

c.694A>G · rs531251219 · VCV2146806

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0749 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0496%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0749	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -6.46	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 -1.2	GERP 0.61
Regional constraint	o/e 0.97	unconstrained · MANE · 33 kb · p 0.33 · regional, not allelic
Overall
CADD	10.75	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 0.0496% Middle Eastern · 3/6,052 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00719%

Overall 0.00192% 31/1,611,090 alleles · ultra-rare exomes 19/1,458,854 · genomes 12/152,236 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0496%	2,017
East Asian	0.0134%	7,469
European (non-Finnish)	0.00178%	56,128
Remaining individualsnot grpmax-eligible	0.0016%	62,432

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.Ile232Val
Coding: c.694A>G
MANE Select: NM_004628
dbSNP: rs531251219
Type: single nucleotide variant
Location: chr3:14165513 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.67 · 18 PDB

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

Similar variants

XPC p.Ile232fs 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
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-ile232val (accessed [today's date]).

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