Is XPC p.Thr689= (c.2067G>A) pathogenic?

XPC p.Thr689= (c.2067G>A) is classified Likely benign in XPC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-31). Ultra-rare (popmax 0.0234%, amr); Associated with xeroderma pigmentosum.

What condition is associated with XPC p.Thr689= (c.2067G>A)?

XPC p.Thr689= (c.2067G>A) is associated with xeroderma pigmentosum (ClinVar).

How common is XPC p.Thr689= (c.2067G>A) in the general population?

XPC p.Thr689= (c.2067G>A) is ultra-rare (popmax 0.0234%, amr) (gnomAD).

How is Xeroderma pigmentosum inherited?

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

XPC p.Thr689=

c.2067G>A · rs765391700 · VCV738320

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0234%, amr)

Conditions

xeroderma pigmentosum

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.043	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -7.5	GERP -3
Overall
CADD	6.32	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0234% Admixed American · 14/59,938 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.00167% 27/1,613,258 alleles · ultra-rare exomes 26/1,460,960 · genomes 1/152,298 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0234%	4,281
East Asian	0.00223%	44,868
South Asian	0.0022%	45,408
European (non-Finnish)	0.000848%	117,961

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.Thr689=
Coding: c.2067G>A
MANE Select: NM_004628
dbSNP: rs765391700
Type: single nucleotide variant
Location: chr3:14152383 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.67 · 18 PDB
Residue 689: the 'interaction with rad23b' region; a UniProt-annotated variant site (in); 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 — 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.Thr689Met Benign/Likely benign ★★ ⚠ same residue
XPC c.2033+1G>A Pathogenic/Likely pathogenic ★★ same condition
XPC c.2251-1G>C Pathogenic ★★ same condition
XPC c.621+1G>A Likely pathogenic ★★ same condition
XPC c.622-2A>C Pathogenic ★★ same condition
XPC p.Arg155Ter Pathogenic ★★ same condition
XPC p.Arg220Ter Pathogenic ★★ same condition
XPC p.Arg293Ter 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-thr689 (accessed [today's date]).

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