Is XPC p.Arg864Pro (c.2591G>C) pathogenic?

XPC p.Arg864Pro (c.2591G>C) is classified Uncertain significance in XPC (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-20). AlphaMissense: likely pathogenic (0.9435); Very rare (popmax 0.00168%, amr); Associated with Inborn genetic diseases.

What condition is associated with XPC p.Arg864Pro (c.2591G>C)?

XPC p.Arg864Pro (c.2591G>C) is associated with Inborn genetic diseases (ClinVar).

How common is XPC p.Arg864Pro (c.2591G>C) in the general population?

XPC p.Arg864Pro (c.2591G>C) is very rare (popmax 0.00168%, amr) (gnomAD).

What do computational predictors say about XPC p.Arg864Pro (c.2591G>C)?

AlphaMissense predicts likely pathogenic (score 0.9435) — an in-silico prediction, not a clinical call.

XPC p.Arg864Pro

c.2591G>C · rs776645102 · VCV2238737

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9435 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00168%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9435	likely pathogenic · top 6% in XPC
REVEL	0.289	benign-leaning
SaProt	LLR -11.03	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 33 kb · p 0.33 · regional, not allelic
Overall
CADD	28.6	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 0.00168% Admixed American · 1/59,566 alleles

Overall 6.21e-05% 1/1,610,510 alleles · very rare exomes 1/1,458,240 · genomes 0/152,270 · joint denominator

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.Arg864Pro
Coding: c.2591G>C
MANE Select: NM_004628
dbSNP: rs776645102
Type: single nucleotide variant
Location: chr3:14147303 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.67 · 18 PDB
Residue 864: the 'interaction with cetn2' region; the 'interaction with ercc2 and gtf2h1' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

XPC p.Arg864His Uncertain significance ★ ⚠ same residue
XPC p.Ala341Gly Uncertain significance ★★ ⚠ same condition
XPC p.Ala341Val Uncertain significance ★★ ⚠ same condition
XPC p.Arg393Gln Uncertain significance ★★ ⚠ same condition
XPC p.Arg858Gly Uncertain significance ★★ same condition
XPC p.Asp885Glu Uncertain significance ★★ ⚠ same condition
XPC p.Gly64Glu Uncertain significance ★★ ⚠ same condition
XPC p.Gly866Arg Uncertain significance ★★ ⚠ 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/xpc-p-arg864pro (accessed [today's date]).

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