Is XPC p.Ala746= (c.2238C>T) pathogenic?

XPC p.Ala746= (c.2238C>T) is classified Conflicting classifications of pathogenicity in XPC (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-20). Ultra-rare (popmax 0.0999%, sas); Associated with xeroderma pigmentosum group C.

What condition is associated with XPC p.Ala746= (c.2238C>T)?

XPC p.Ala746= (c.2238C>T) is associated with xeroderma pigmentosum group C, xeroderma pigmentosum (ClinVar).

How common is XPC p.Ala746= (c.2238C>T) in the general population?

XPC p.Ala746= (c.2238C>T) is ultra-rare (popmax 0.0999%, sas) (gnomAD).

How is Xeroderma pigmentosum inherited?

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

XPC p.Ala746=

c.2238C>T · rs375170067 · VCV731076

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0999%, sas)

Conditions

xeroderma pigmentosum group C

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.1	GERP -3.1
Overall
CADD	4.958	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0999% South Asian · 91/91,078 alleles

Filtering AF 0.0833% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0771%

Overall 0.0182% 294/1,613,982 alleles · ultra-rare exomes 274/1,461,670 · genomes 20/152,312 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0999%	1,001
European (non-Finnish)	0.0162%	6,177
Remaining individualsnot grpmax-eligible	0.0144%	6,943
African / African-American	0.004%	25,018

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.Ala746=
Coding: c.2238C>T
MANE Select: NM_004628
dbSNP: rs375170067
Type: single nucleotide variant
Location: chr3:14148826 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.67 · 18 PDB
Residue 746: the 'minimal sensor domain involved in damage recognition' 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

Also linked: xeroderma pigmentosum

For Xeroderma pigmentosum (Orphanet):

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

Similar variants

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
XPC c.413-24A>G 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-ala746 (accessed [today's date]).

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