Is DKK1 p.Ala98Pro (c.292G>C) pathogenic?

DKK1 p.Ala98Pro (c.292G>C) is classified Uncertain significance in DKK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: ambiguous (0.5218); Ultra-rare (popmax 0.0838%, mid).

How common is DKK1 p.Ala98Pro (c.292G>C) in the general population?

DKK1 p.Ala98Pro (c.292G>C) is ultra-rare (popmax 0.0838%, mid) (gnomAD).

What do computational predictors say about DKK1 p.Ala98Pro (c.292G>C)?

AlphaMissense predicts ambiguous (score 0.5218) — an in-silico prediction, not a clinical call.

DKK1 p.Ala98Pro

c.292G>C · rs746154609 · VCV2360989

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5218 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0838%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5218	ambiguous
REVEL	0.029	moderately benign-leaning
SaProt	LLR -10.13	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP -3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 2,369 bp · p 0.47 · regional, not allelic
Overall
CADD	18.32	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 0.0838% Middle Eastern · 5/5,970 alleles

Filtering AF 0.0329% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00706% 113/1,600,892 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0838%	1,194
Admixed American	0.0135%	7,416
European (non-Finnish)	0.0082%	12,202
Remaining individualsnot grpmax-eligible	0.00323%	30,913
Finnishnot grpmax-eligible	0.00158%	63,280
South Asian	0.00111%	89,790

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: DKK1
Protein: p.Ala98Pro
Coding: c.292G>C
MANE Select: NM_012242
dbSNP: rs746154609
Type: single nucleotide variant
Location: chr10:52314971 (GRCh38)
Gene constraint: LOEUF 1.101 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.68 · 5 PDB
Residue 98: the 'dkk-type cys-1' region; a disulfide bond

Full DKK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DKK1 c.244-6C>T Benign ★★ same type
DKK1 c.548-4G>A Benign/Likely benign ★★ same type
DKK1 p.Ala113Thr Conflicting classifications of pathogenicity ★ ⚠ same type
DKK1 p.Ala196Val Uncertain significance ★ ⚠ same type
DKK1 p.Ala19Thr Uncertain significance ★ ⚠ same type
DKK1 p.Arg115Lys Uncertain significance ★ ⚠ same type
DKK1 p.Arg11Gln Uncertain significance ★ ⚠ same type
DKK1 p.Arg246Trp Uncertain significance ★ ⚠ same type

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/dkk1-p-ala98pro (accessed [today's date]).

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