Is DACT2 p.Ser136Pro (c.406T>C) pathogenic?

DACT2 p.Ser136Pro (c.406T>C) is classified Uncertain significance in DACT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-18). AlphaMissense: ambiguous (0.5583); Ultra-rare (popmax 0.0669%, mid).

How common is DACT2 p.Ser136Pro (c.406T>C) in the general population?

DACT2 p.Ser136Pro (c.406T>C) is ultra-rare (popmax 0.0669%, mid) (gnomAD).

What do computational predictors say about DACT2 p.Ser136Pro (c.406T>C)?

AlphaMissense predicts ambiguous (score 0.5583) — an in-silico prediction, not a clinical call.

DACT2 p.Ser136Pro

c.406T>C · rs745324019 · VCV3079970

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5583 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0669%, mid)

Computational evidence

Protein change
AlphaMissense	0.5583	ambiguous
REVEL	0.422	indeterminate
SaProt	LLR -8.13	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 12 kb · p 0.68 · regional, not allelic
Overall
CADD	25.5	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 0.0669% Middle Eastern · 4/5,976 alleles

Filtering AF 0.0229% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.000838% 13/1,551,014 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0669%	1,494
South Asian	0.00357%	27,980
Ashkenazi Jewishnot grpmax-eligible	0.0035%	28,600
Remaining individualsnot grpmax-eligible	0.00333%	30,046
European (non-Finnish)	0.000262%	382,244

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: DACT2
Protein: p.Ser136Pro
Coding: c.406T>C
MANE Select: NM_214462
dbSNP: rs745324019
Type: single nucleotide variant
Location: chr6:168310420 (GRCh38)
Gene constraint: LOEUF 1.469 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.81

Full DACT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DACT2 p.Ala11Thr Uncertain significance ★ ⚠ same type
DACT2 p.Ala162Thr Uncertain significance ★ ⚠ same type
DACT2 p.Ala186Val Uncertain significance ★ ⚠ same type
DACT2 p.Ala228Val Uncertain significance ★ ⚠ same type
DACT2 p.Ala239Thr Uncertain significance ★ ⚠ same type
DACT2 p.Ala283Val Uncertain significance ★ ⚠ same type
DACT2 p.Ala312Thr Uncertain significance ★ ⚠ same type
DACT2 p.Ala332Thr 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/dact2-p-ser136pro (accessed [today's date]).

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