Is DACT1 p.Arg656Gly (c.1966A>G) pathogenic?

DACT1 p.Arg656Gly (c.1966A>G) is classified Uncertain significance in DACT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-08). AlphaMissense: ambiguous (0.5591); Ultra-rare (popmax 0.0267%, amr).

How common is DACT1 p.Arg656Gly (c.1966A>G) in the general population?

DACT1 p.Arg656Gly (c.1966A>G) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

What do computational predictors say about DACT1 p.Arg656Gly (c.1966A>G)?

AlphaMissense predicts ambiguous (score 0.5591) — an in-silico prediction, not a clinical call.

DACT1 p.Arg656Gly

c.1966A>G · VCV4658372

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5591 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5591	ambiguous
REVEL	0.282	benign-leaning
SaProt	LLR -10.73	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.24	GERP -5.2
Regional constraint	o/e 1.10	unconstrained · MANE · 8,733 bp · p 0.0021 · regional, not allelic
Overall
CADD	14.45	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R693G vs ClinVar R656G) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0267% Admixed American · 16/59,986 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.000992% 16/1,613,046 alleles · ultra-rare

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: DACT1
Protein: p.Arg656Gly
Coding: c.1966A>G
MANE Select: NM_001079520
Type: single nucleotide variant
Location: chr14:58646700 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 50.95
Residue 656: a UniProt-annotated variant site (in tbs2; the mutant protein is stable and expressed); the 'disordered' region

Full DACT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DACT1 p.Glu451Asp Uncertain significance ★★ ⚠ same type
DACT1 c.635-121T>C Likely benign ★★ same type
DACT1 p.Ala427Val Benign ★★ same type
DACT1 p.Ala500= Benign ★★ same type
DACT1 p.Asp409Asn Benign ★★ same type
DACT1 p.Glu257Lys Benign/Likely benign ★★ same type
DACT1 p.Glu49= Likely benign ★★ same type
DACT1 p.Gly660Ser Benign ★★ 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/dact1-p-arg656gly (accessed [today's date]).

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