Is XPC p.Pro417Leu (c.1250C>T) pathogenic?

XPC p.Pro417Leu (c.1250C>T) is classified Conflicting classifications of pathogenicity in XPC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-10-15). AlphaMissense: likely benign (0.075); Rare (popmax 0.363%, mid); Associated with xeroderma pigmentosum group C.

What condition is associated with XPC p.Pro417Leu (c.1250C>T)?

XPC p.Pro417Leu (c.1250C>T) is associated with xeroderma pigmentosum group C (ClinVar).

How common is XPC p.Pro417Leu (c.1250C>T) in the general population?

XPC p.Pro417Leu (c.1250C>T) is rare (popmax 0.363%, mid) (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.Pro417Leu (c.1250C>T)?

AlphaMissense predicts likely benign (score 0.075) — an in-silico prediction, not a clinical call.

XPC p.Pro417Leu

c.1250C>T · rs376830678 · VCV2361298

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.075 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.363%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xeroderma pigmentosum group C

Computational evidence

Protein change
AlphaMissense	0.075	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -6.43	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 -3.8	GERP -2.7
Regional constraint	o/e 0.97	unconstrained · MANE · 33 kb · p 0.33 · regional, not allelic
Overall
CADD	0.936	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 0.363% Middle Eastern · 22/6,062 alleles

Filtering AF 0.246% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.207%

Overall 0.0075% 121/1,613,848 alleles · rare exomes 70/1,461,692 · genomes 51/152,156 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.363%	276
African / African-American	0.107%	938
Remaining individualsnot grpmax-eligible	0.0112%	8,927
Admixed American	0.005%	20,005
South Asian	0.00439%	22,769
European (non-Finnish)	0.000424%	235,974

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.Pro417Leu
Coding: c.1250C>T
MANE Select: NM_004628
dbSNP: rs376830678
Type: single nucleotide variant
Location: chr3:14158633 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.67 · 18 PDB
Residue 417: the 'disordered' region

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.Pro417= 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
XPC c.299+1G>A 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-pro417leu (accessed [today's date]).

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