Is XPC p.Ala499= (c.1497G>A) pathogenic?

XPC p.Ala499= (c.1497G>A) is classified Benign/Likely benign in XPC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-26). Rare (popmax 0.391%, afr); Associated with xeroderma pigmentosum group C.

What condition is associated with XPC p.Ala499= (c.1497G>A)?

XPC p.Ala499= (c.1497G>A) is associated with xeroderma pigmentosum group C, xeroderma pigmentosum (ClinVar).

How common is XPC p.Ala499= (c.1497G>A) in the general population?

XPC p.Ala499= (c.1497G>A) is rare (popmax 0.391%, afr) (gnomAD).

How is Xeroderma pigmentosum inherited?

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

XPC p.Ala499=

c.1497G>A · rs150344169 · VCV785035

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.391%, afr)

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 -2.1	GERP -3.2
Overall
CADD	1.243	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.391% African / African-American · 293/74,998 alleles

Filtering AF 0.354% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.339%

Overall 0.0263% 425/1,613,868 alleles · rare exomes 244/1,461,672 · genomes 181/152,196 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.391%	256
South Asian	0.0615%	1,627
Remaining individualsnot grpmax-eligible	0.0448%	2,232
Middle Eastern	0.033%	3,031
Admixed American	0.03%	3,334
European (non-Finnish)	0.00237%	42,139

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.Ala499=
Coding: c.1497G>A
MANE Select: NM_004628
dbSNP: rs150344169
Type: single nucleotide variant
Location: chr3:14158386 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.67 · 18 PDB
Residue 499: the 'disordered' region; a UniProt-annotated variant site (in); the 'interaction with rad23b' 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 p.Ala499Val Benign/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-ala499 (accessed [today's date]).

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