Is XPC p.Pro645Ala (c.1933C>G) pathogenic?

XPC p.Pro645Ala (c.1933C>G) is classified Likely pathogenic in XPC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-01). AlphaMissense: likely pathogenic (0.6364); Ultra-rare (popmax 0.0164%, mid); Associated with ovarian cancer.

What condition is associated with XPC p.Pro645Ala (c.1933C>G)?

XPC p.Pro645Ala (c.1933C>G) is associated with ovarian cancer (ClinVar).

How common is XPC p.Pro645Ala (c.1933C>G) in the general population?

XPC p.Pro645Ala (c.1933C>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about XPC p.Pro645Ala (c.1933C>G)?

AlphaMissense predicts likely pathogenic (score 0.6364) — an in-silico prediction, not a clinical call.

XPC p.Pro645Ala

c.1933C>G · rs762099392 · VCV2445342

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6364 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.6364	likely pathogenic ✓ concordant with ClinVar
REVEL	0.722	pathogenic-leaning
SaProt	LLR -12.53	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 33 kb · p 0.33 · regional, not allelic
Overall
CADD	25.8	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000867% 14/1,613,920 alleles · ultra-rare exomes 13/1,461,688 · genomes 1/152,232 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
East Asian	0.00223%	44,894
African / African-American	0.00133%	74,940
European (non-Finnish)	0.000932%	107,264

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.Pro645Ala
Coding: c.1933C>G
MANE Select: NM_004628
dbSNP: rs762099392
Type: single nucleotide variant
Location: chr3:14156435 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.67 · 18 PDB
Residue 645: 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

Disease context

ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

XPC p.Arg423Trp Conflicting classifications of pathogenicity ★ ⚠ same condition
XPC p.Val813Ile Conflicting classifications of pathogenicity ★ ⚠ same condition
XPC p.Glu721Asp Benign ★ same condition
XPC p.His111Leu Benign ★ same condition
XPC p.Pro645fs 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

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-pro645ala (accessed [today's date]).

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