Is XPC p.Pro334Ser (c.1000C>T) pathogenic?

XPC p.Pro334Ser (c.1000C>T) is classified Benign/Likely benign in XPC (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0714); Rare (popmax 0.784%, sas); Associated with xeroderma pigmentosum.

What condition is associated with XPC p.Pro334Ser (c.1000C>T)?

XPC p.Pro334Ser (c.1000C>T) is associated with xeroderma pigmentosum, xeroderma pigmentosum group C (ClinVar).

How common is XPC p.Pro334Ser (c.1000C>T) in the general population?

XPC p.Pro334Ser (c.1000C>T) is rare (popmax 0.784%, sas) (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.Pro334Ser (c.1000C>T)?

AlphaMissense predicts likely benign (score 0.0714) — an in-silico prediction, not a clinical call.

XPC p.Pro334Ser

c.1000C>T · rs200338014 · VCV135487

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0714 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.784%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xeroderma pigmentosum

Computational evidence

Protein change
AlphaMissense	0.0714	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -5.31	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 0.24	GERP -2.9, phastCons 0.005
Regional constraint	o/e 0.97	unconstrained · MANE · 33 kb · p 0.33 · regional, not allelic
Overall
CADD	1.958	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 0.784% South Asian · 714/91,078 alleles

Filtering AF 0.736% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.717%

Overall 0.0459% 741/1,613,876 alleles · rare exomes 701/1,461,680 · genomes 40/152,196 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.784%	128
Remaining individualsnot grpmax-eligible	0.0336%	2,975
Middle Eastern	0.0331%	3,020
African / African-American	0.00133%	75,014
European (non-Finnish)	0.000254%	393,290

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.Pro334Ser
Coding: c.1000C>T
MANE Select: NM_004628
dbSNP: rs200338014
Type: single nucleotide variant
Location: chr3:14158883 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.67 · 18 PDB
Residue 334: the 'disordered' region; a UniProt-annotated variant site (in xp-c; severe; does not affect interaction with kat2a and transcription coactivator activity in absence of dna damage)

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

Disease context

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

Also linked: xeroderma pigmentosum group C

For Xeroderma pigmentosum (Orphanet):

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

Similar variants

XPC p.Pro334His Benign/Likely benign ★★ same residue
XPC p.Pro334Leu Uncertain significance ★ ⚠ 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-pro334ser (accessed [today's date]).

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