Is XPC p.Pro645fs (c.1934del) pathogenic?

XPC p.Pro645fs (c.1934del) is classified Likely pathogenic in XPC (ClinVar, No assertion criteria, 1 submitter; last evaluated 2017-12-08). Very rare (popmax 0.00329%, sas); Associated with xeroderma pigmentosum group C.

What condition is associated with XPC p.Pro645fs (c.1934del)?

XPC p.Pro645fs (c.1934del) is associated with xeroderma pigmentosum group C (ClinVar).

How common is XPC p.Pro645fs (c.1934del) in the general population?

XPC p.Pro645fs (c.1934del) is very rare (popmax 0.00329%, sas) (gnomAD).

How is Xeroderma pigmentosum inherited?

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

XPC p.Pro645fs

c.1934del · rs1553605497 · VCV555481

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

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 0.055	GERP -3.7, phastCons 0.088
Overall
CADD	34.0	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 0.00329% South Asian · 3/91,080 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00031% 5/1,613,880 alleles · very rare exomes 4/1,461,692 · genomes 1/152,188 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,360
Admixed American	0.00167%	60,002
European (non-Finnish)	8.48e-05%	1,179,901

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.Pro645fs
Coding: c.1934del
MANE Select: NM_004628
dbSNP: rs1553605497
Type: Deletion
Location: chr3:14156434 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.67 · 18 PDB
Residue 645: 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.Ala674fs Pathogenic/Likely pathogenic ★★ same condition
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-pro645fs (accessed [today's date]).

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