Is XPC p.Arg908Pro (c.2723G>C) pathogenic?

XPC p.Arg908Pro (c.2723G>C) is classified Uncertain significance in XPC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-06). AlphaMissense: likely pathogenic (0.7131); Very rare (popmax 0.00017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with XPC p.Arg908Pro (c.2723G>C)?

XPC p.Arg908Pro (c.2723G>C) is associated with Inborn genetic diseases (ClinVar).

How common is XPC p.Arg908Pro (c.2723G>C) in the general population?

XPC p.Arg908Pro (c.2723G>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about XPC p.Arg908Pro (c.2723G>C)?

AlphaMissense predicts likely pathogenic (score 0.7131) — an in-silico prediction, not a clinical call.

XPC p.Arg908Pro

c.2723G>C · rs1238647795 · VCV2494691

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7131 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7131	likely pathogenic
REVEL	0.215	benign-leaning
SaProt	LLR -4.98	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 33 kb · p 0.33 · regional, not allelic
Overall
CADD	25.7	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 0.00017% European (non-Finnish) · 2/1,179,416 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,612,800 alleles · very rare exomes 2/1,460,982 · genomes 0/151,818 · 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.Arg908Pro
Coding: c.2723G>C
MANE Select: NM_004628
dbSNP: rs1238647795
Type: single nucleotide variant
Location: chr3:14146041 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.67 · 18 PDB
Residue 908: the 'disordered' region; a turn; 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.Arg908Ter Uncertain significance ★ same residue
XPC p.Arg908= Likely benign ★ 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

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-arg908pro (accessed [today's date]).

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