Is DACT2 p.Ala725Val (c.2174C>T) pathogenic?

DACT2 p.Ala725Val (c.2174C>T) is classified Uncertain significance in DACT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-21). AlphaMissense: likely benign (0.0833); Ultra-rare (popmax 0.0392%, eas).

How common is DACT2 p.Ala725Val (c.2174C>T) in the general population?

DACT2 p.Ala725Val (c.2174C>T) is ultra-rare (popmax 0.0392%, eas) (gnomAD).

What do computational predictors say about DACT2 p.Ala725Val (c.2174C>T)?

AlphaMissense predicts likely benign (score 0.0833) — an in-silico prediction, not a clinical call.

DACT2 p.Ala725Val

c.2174C>T · rs761233827 · VCV2259186

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0833 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0392%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0833	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -7.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.19	GERP -3.5
Regional constraint	o/e 0.99	unconstrained · MANE · 12 kb · p 0.68 · regional, not allelic
Overall
CADD	4.835	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0392% East Asian · 16/40,866 alleles

Filtering AF 0.0245% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0199%

Overall 0.00478% 74/1,549,732 alleles · ultra-rare exomes 71/1,397,638 · genomes 3/152,094 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0392%	2,554
South Asian	0.0286%	3,496
Remaining individualsnot grpmax-eligible	0.005%	19,997
European (non-Finnish)	0.0027%	36,978

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.Ala725Val
Coding: c.2174C>T
MANE Select: NM_214462
dbSNP: rs761233827
Type: single nucleotide variant
Location: chr6:168307583 (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.Ala725Glu Uncertain significance ★ ⚠ same residue
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

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-ala725val (accessed [today's date]).

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