Is DKK2 p.Cys189Ser (c.566G>C) pathogenic?

DKK2 p.Cys189Ser (c.566G>C) is classified Uncertain significance in DKK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-12). AlphaMissense: likely pathogenic (0.9993); Very rare (popmax 0.000124%).

How common is DKK2 p.Cys189Ser (c.566G>C) in the general population?

DKK2 p.Cys189Ser (c.566G>C) is very rare (popmax 0.000124%) (gnomAD).

What do computational predictors say about DKK2 p.Cys189Ser (c.566G>C)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

DKK2 p.Cys189Ser

c.566G>C · rs772632334 · VCV2622616

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000124%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic · top 1% in DKK2
REVEL	0.874	moderately pathogenic-leaning
SaProt	LLR -13.72	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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 112 kb · p 0.6 · regional, not allelic
Overall
CADD	27.2	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 0.000124%

Overall 0.000124% 2/1,613,782 alleles · very rare

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: DKK2
Protein: p.Cys189Ser
Coding: c.566G>C
MANE Select: NM_014421
dbSNP: rs772632334
Type: single nucleotide variant
Location: chr4:106924168 (GRCh38)
Gene constraint: LOEUF 0.621 · pLI 0.61 (gnomAD)
Structure: AlphaFold pLDDT 70.82
Residue 189: the 'dkk-type cys-2' region; a disulfide bond

Full DKK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DKK2 p.Ala3Thr Uncertain significance ★ ⚠ same type
DKK2 p.Ala75Thr Uncertain significance ★ ⚠ same type
DKK2 p.Arg104Gln Uncertain significance ★ ⚠ same type
DKK2 p.Arg218Cys Uncertain significance ★ ⚠ same type
DKK2 p.Asn36Lys Uncertain significance ★ ⚠ same type
DKK2 p.Asp232Asn Uncertain significance ★ ⚠ same type
DKK2 p.Asp244Glu Uncertain significance ★ ⚠ same type
DKK2 p.Asp9Tyr 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/dkk2-p-cys189ser (accessed [today's date]).

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