Is DKK4 p.Ser177Pro (c.529T>C) pathogenic?

DKK4 p.Ser177Pro (c.529T>C) is classified Uncertain significance in DKK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). AlphaMissense: likely pathogenic (0.8554); Ultra-rare (popmax 0.0166%, mid).

How common is DKK4 p.Ser177Pro (c.529T>C) in the general population?

DKK4 p.Ser177Pro (c.529T>C) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about DKK4 p.Ser177Pro (c.529T>C)?

AlphaMissense predicts likely pathogenic (score 0.8554) — an in-silico prediction, not a clinical call.

DKK4 p.Ser177Pro

c.529T>C · rs375323773 · VCV3082650

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8554 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8554	likely pathogenic
REVEL	0.527	indeterminate
SaProt	LLR -6.24	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP -0.37, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 2,942 bp · p 0.62 · regional, not allelic
Overall
CADD	24.9	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 0.0166% Middle Eastern · 1/6,034 alleles

Filtering AF 0.00165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00211% 34/1,612,002 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,034
Admixed American	0.00501%	19,952
Remaining individualsnot grpmax-eligible	0.00321%	31,188
European (non-Finnish)	0.00237%	42,108

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: DKK4
Protein: p.Ser177Pro
Coding: c.529T>C
MANE Select: NM_014420
dbSNP: rs375323773
Type: single nucleotide variant
Location: chr8:42374246 (GRCh38)
Gene constraint: LOEUF 1.636 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.72 · 2 PDB
Residue 177: a disulfide bond; the 'dkk-type cys-2' region

Full DKK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DKK4 p.Ala30Thr Uncertain significance ★ ⚠ same type
DKK4 p.Arg102Ser Uncertain significance ★ ⚠ same type
DKK4 p.Arg159His Uncertain significance ★ same type
DKK4 p.Arg159Ser Uncertain significance ★ ⚠ same type
DKK4 p.Arg179Ser Uncertain significance ★ ⚠ same type
DKK4 p.Arg210Trp Uncertain significance ★ ⚠ same type
DKK4 p.Arg36Trp Uncertain significance ★ ⚠ same type
DKK4 p.Arg57Cys 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/dkk4-p-ser177pro (accessed [today's date]).

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