Is DKK3 p.Pro266Ser (c.796C>T) pathogenic?

DKK3 p.Pro266Ser (c.796C>T) is classified Uncertain significance in DKK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-01). AlphaMissense: ambiguous (0.5044); Very rare (popmax 0.00833%, amr).

How common is DKK3 p.Pro266Ser (c.796C>T) in the general population?

DKK3 p.Pro266Ser (c.796C>T) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about DKK3 p.Pro266Ser (c.796C>T)?

AlphaMissense predicts ambiguous (score 0.5044) — an in-silico prediction, not a clinical call.

DKK3 p.Pro266Ser

c.796C>T · VCV4011930

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5044 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5044	ambiguous
REVEL	0.646	pathogenic-leaning
SaProt	LLR -7.68	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 44 kb · p 0.0048 · regional, not allelic
Overall
CADD	28.5	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 0.00833% Admixed American · 5/60,034 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.00041% 6/1,461,814 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,007
East Asian	0.00223%	44,874

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: DKK3
Protein: p.Pro266Ser
Coding: c.796C>T
MANE Select: NM_001018057
Type: single nucleotide variant
Location: chr11:11965843 (GRCh38)
Gene constraint: LOEUF 0.955 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.08
Residue 266: a disulfide bond; the 'dkk-type cys-2' region

Full DKK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DKK3 p.Glu307Gly Benign ★★ same type
DKK3 p.Ala14Glu Uncertain significance ★ ⚠ same type
DKK3 p.Ala14Thr Uncertain significance ★ ⚠ same type
DKK3 p.Ala14Val Uncertain significance ★ ⚠ same type
DKK3 p.Ala245Thr Uncertain significance ★ ⚠ same type
DKK3 p.Ala338Val Uncertain significance ★ ⚠ same type
DKK3 p.Ala342Thr Uncertain significance ★ ⚠ same type
DKK3 p.Ala74Glu 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/dkk3-p-pro266ser (accessed [today's date]).

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