Is XPC p.Lys642Glu (c.1924A>G) pathogenic?

XPC p.Lys642Glu (c.1924A>G) is classified Uncertain significance in XPC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). AlphaMissense: likely pathogenic (0.9486); Ultra-rare (popmax 0.025%, amr); Associated with Inborn genetic diseases.

What condition is associated with XPC p.Lys642Glu (c.1924A>G)?

XPC p.Lys642Glu (c.1924A>G) is associated with Inborn genetic diseases (ClinVar).

How common is XPC p.Lys642Glu (c.1924A>G) in the general population?

XPC p.Lys642Glu (c.1924A>G) is ultra-rare (popmax 0.025%, amr) (gnomAD).

What do computational predictors say about XPC p.Lys642Glu (c.1924A>G)?

AlphaMissense predicts likely pathogenic (score 0.9486) — an in-silico prediction, not a clinical call.

XPC p.Lys642Glu

c.1924A>G · VCV3982819

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9486 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9486	likely pathogenic · top 6% in XPC
REVEL	0.849	moderately pathogenic-leaning
SaProt	LLR -14.72	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 33 kb · p 0.33 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.025% Admixed American · 15/60,008 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.000991% 16/1,613,858 alleles · ultra-rare exomes 15/1,461,684 · genomes 1/152,174 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.025%	4,001
Remaining individualsnot grpmax-eligible	0.0016%	62,464

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.Lys642Glu
Coding: c.1924A>G
MANE Select: NM_004628
Type: single nucleotide variant
Location: chr3:14156444 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.67 · 18 PDB
Residue 642: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

XPC p.Ala341Gly Uncertain significance ★★ ⚠ same condition
XPC p.Ala341Val Uncertain significance ★★ ⚠ same condition
XPC p.Arg393Gln Uncertain significance ★★ ⚠ same condition
XPC p.Arg858Gly Uncertain significance ★★ same condition
XPC p.Asp885Glu Uncertain significance ★★ ⚠ same condition
XPC p.Gly64Glu Uncertain significance ★★ ⚠ same condition
XPC p.Gly866Arg Uncertain significance ★★ ⚠ same condition
XPC p.Lys927Asn Uncertain significance ★★ ⚠ 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-lys642glu (accessed [today's date]).

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