Is XPC p.Pro633Ser (c.1897C>T) pathogenic?

XPC p.Pro633Ser (c.1897C>T) is classified Benign in XPC (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-05). AlphaMissense: ambiguous (0.491); Very rare (popmax 8.48e-05%, nfe); Associated with xeroderma pigmentosum group C.

What condition is associated with XPC p.Pro633Ser (c.1897C>T)?

XPC p.Pro633Ser (c.1897C>T) is associated with xeroderma pigmentosum group C (ClinVar).

How common is XPC p.Pro633Ser (c.1897C>T) in the general population?

XPC p.Pro633Ser (c.1897C>T) 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.

What do computational predictors say about XPC p.Pro633Ser (c.1897C>T)?

AlphaMissense predicts ambiguous (score 0.491) — an in-silico prediction, not a clinical call.

XPC p.Pro633Ser

c.1897C>T · rs749104732 · VCV1684238

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.491 · ACMG-weighted

gnomAD v4.1

Rare

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

Conditions

xeroderma pigmentosum group C

Computational evidence

Protein change
AlphaMissense	0.491	ambiguous
REVEL	0.407	indeterminate
SaProt	LLR -11.60	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 33 kb · p 0.33 · regional, not allelic
Overall
CADD	24.9	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 8.48e-05% European (non-Finnish) · 1/1,179,878 alleles

Overall 0.00031% 5/1,614,026 alleles · very rare exomes 5/1,461,672 · genomes 0/152,354 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,621
European (non-Finnish)grpmax	8.48e-05%	1,179,878

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro633Ser
Coding: c.1897C>T
MANE Select: NM_004628
dbSNP: rs749104732
Type: single nucleotide variant
Location: chr3:14156471 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.67 · 18 PDB
Residue 633: 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.Pro633fs Pathogenic/Likely pathogenic ★★ 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-pro633ser (accessed [today's date]).

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