Is XPC p.Ala674fs (c.2020_2029del) pathogenic?

XPC p.Ala674fs (c.20202029del) is classified Pathogenic/Likely pathogenic in XPC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-27). Very rare (popmax 8.48e-05%, nfe); Associated with xeroderma pigmentosum group C.

What condition is associated with XPC p.Ala674fs (c.2020_2029del)?

XPC p.Ala674fs (c.2020_2029del) is associated with xeroderma pigmentosum group C (ClinVar).

How common is XPC p.Ala674fs (c.2020_2029del) in the general population?

XPC p.Ala674fs (c.2020_2029del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Xeroderma pigmentosum inherited?

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

XPC p.Ala674fs

c.2020_2029del · rs1246211702 · VCV1947826

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

xeroderma pigmentosum group C

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,660 alleles

Overall 6.2e-05% 1/1,613,424 alleles · very rare exomes 0/1,461,254 · genomes 1/152,170 · joint denominator

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.Ala674fs
Coding: c.2020_2029del
MANE Select: NM_004628
dbSNP: rs1246211702
Type: Deletion
Location: chr3:14156339 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.67 · 18 PDB
Residue 674: the 'interaction with rad23b' region; the 'minimal sensor domain involved in damage recognition' region; the 'dna-binding; preference for heteroduplex dna' 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.Ala674Ser Uncertain significance ★ ⚠ same residue
XPC p.Arg314fs Pathogenic ★★ same condition
XPC p.Arg423fs Pathogenic/Likely pathogenic ★★ same condition
XPC p.Asp121fs Pathogenic/Likely pathogenic ★★ same condition
XPC p.Gln368fs Pathogenic ★★ same condition
XPC p.Gln742fs Pathogenic ★★ same condition
XPC p.Glu141fs Pathogenic ★★ same condition
XPC p.Glu726fs 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-ala674fs (accessed [today's date]).

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