Is DACT2 p.Ala655Thr (c.1963G>A) pathogenic?

DACT2 p.Ala655Thr (c.1963G>A) is classified Uncertain significance in DACT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-06). AlphaMissense: likely benign (0.0777); Ultra-rare (popmax 0.0137%, amr).

How common is DACT2 p.Ala655Thr (c.1963G>A) in the general population?

DACT2 p.Ala655Thr (c.1963G>A) is ultra-rare (popmax 0.0137%, amr) (gnomAD).

What do computational predictors say about DACT2 p.Ala655Thr (c.1963G>A)?

AlphaMissense predicts likely benign (score 0.0777) — an in-silico prediction, not a clinical call.

DACT2 p.Ala655Thr

c.1963G>A · VCV4009246

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0777 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0137%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0777	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -3.79	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 -1.4	GERP -3.4
Regional constraint	o/e 0.99	unconstrained · MANE · 12 kb · p 0.68 · regional, not allelic
Overall
CADD	7.995	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 0.0137% Admixed American · 7/50,924 alleles

Filtering AF 0.00901% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00844%

Overall 0.00855% 132/1,543,050 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0137%	7,275
European (non-Finnish)	0.0106%	9,474
African / African-American	0.00274%	36,498
Finnishnot grpmax-eligible	0.00191%	52,470
Remaining individualsnot grpmax-eligible	0.00167%	60,004

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.Ala655Thr
Coding: c.1963G>A
MANE Select: NM_214462
Type: single nucleotide variant
Location: chr6:168307794 (GRCh38)
Gene constraint: LOEUF 1.469 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.81
Residue 655: the 'disordered' region

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-ala655thr (accessed [today's date]).

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