Is XPC p.Arg314Trp (c.940C>T) pathogenic?

XPC p.Arg314Trp (c.940C>T) is classified Uncertain significance in XPC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-03-31). AlphaMissense: likely pathogenic (0.839); Very rare (popmax 0.00762%, amr); Associated with xeroderma pigmentosum group C.

What condition is associated with XPC p.Arg314Trp (c.940C>T)?

XPC p.Arg314Trp (c.940C>T) is associated with xeroderma pigmentosum group C (ClinVar).

How common is XPC p.Arg314Trp (c.940C>T) in the general population?

XPC p.Arg314Trp (c.940C>T) is very rare (popmax 0.00762%, amr) (gnomAD).

How is Xeroderma pigmentosum inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about XPC p.Arg314Trp (c.940C>T)?

AlphaMissense predicts likely pathogenic (score 0.839) — an in-silico prediction, not a clinical call.

XPC p.Arg314Trp

c.940C>T · rs914274804 · VCV902588

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.839 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00762%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

xeroderma pigmentosum group C

Computational evidence

Protein change
AlphaMissense	0.839	likely pathogenic
REVEL	0.639	indeterminate
SaProt	LLR -14.22	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 0.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 33 kb · p 0.33 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00762% Admixed American · 4/52,462 alleles

Filtering AF 0.00258% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00282% 44/1,562,082 alleles · very rare exomes 43/1,409,884 · genomes 1/152,198 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00762%	13,115
East Asian	0.00479%	20,890
South Asian	0.00355%	28,197
European (non-Finnish)	0.00286%	34,938
Remaining individualsnot grpmax-eligible	0.00165%	60,606
African / African-American	0.00136%	73,432

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.Arg314Trp
Coding: c.940C>T
MANE Select: NM_004628
dbSNP: rs914274804
Type: single nucleotide variant
Location: chr3:14159791 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.67 · 18 PDB
Residue 314: a UniProt-annotated variant site (in)

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

Disease context

xeroderma pigmentosum group C — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Xeroderma pigmentosum (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

XPC p.Arg314fs Pathogenic ★★ same residue
XPC p.Arg314= Likely benign ★ same residue
XPC c.104-2A>G Likely pathogenic ★★ same condition
XPC c.1872+1G>A Likely pathogenic ★★ same condition
XPC c.1872+1G>C Pathogenic/Likely pathogenic ★★ same condition
XPC c.2033+1G>A Pathogenic/Likely pathogenic ★★ same condition
XPC c.2251-1G>C Pathogenic ★★ same condition
XPC c.2420+2T>C Pathogenic/Likely pathogenic ★★ 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-arg314trp (accessed [today's date]).

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