Is DACT1 p.Ser591Ala (c.1771T>G) pathogenic?

DACT1 p.Ser591Ala (c.1771T>G) is classified Benign in DACT1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-02-18). AlphaMissense: likely benign (0.0578); Common (popmax 8.31%, afr) — too common for a highly-penetrant pathogenic allele; Associated with DACT1-related disorder.

What condition is associated with DACT1 p.Ser591Ala (c.1771T>G)?

DACT1 p.Ser591Ala (c.1771T>G) is associated with DACT1-related disorder (ClinVar).

What do computational predictors say about DACT1 p.Ser591Ala (c.1771T>G)?

AlphaMissense predicts likely benign (score 0.0578) — an in-silico prediction, not a clinical call.

DACT1 p.Ser591Ala

Q: How common is DACT1 p.Ser591Ala (c.1771T>G) in the general population?

DACT1 p.Ser591Ala (c.1771T>G) is common (popmax 8.31%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1771T>G · rs17094821 · VCV3037405

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0578 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 8.31%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DACT1-related disorder

Computational evidence

Protein change
AlphaMissense	0.0578	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -6.56	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 -0.34	GERP -4.8
Regional constraint	o/e 1.10	unconstrained · MANE · 8,733 bp · p 0.0021 · regional, not allelic
Overall
CADD	0.917	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 S628A vs ClinVar S591A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.31% African / African-American · 5,987/72,082 alleles

Filtering AF 8.13% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.06%

Overall 0.445% 6,941/1,558,266 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	8.31%	12
Remaining individualsnot grpmax-eligible	0.596%	168
Admixed American	0.511%	196
Middle Eastern	0.371%	270
South Asian	0.0478%	2,092
European (non-Finnish)	0.0252%	3,963
East Asian	0.00235%	42,504

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.Ser591Ala
Coding: c.1771T>G
MANE Select: NM_001079520
dbSNP: rs17094821
Type: single nucleotide variant
Location: chr14:58646505 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 50.95
Residue 591: 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

Disease context

DACT1-related disorder

Similar variants

DACT1 p.Ala9Pro Uncertain significance ★ ⚠ same condition
DACT1 p.His426Arg Uncertain significance ★ ⚠ same condition
DACT1 p.Pro295Ala Uncertain significance ★ ⚠ same condition
DACT1 p.Ala677Ser Uncertain significance ⚠ same condition
DACT1 p.Arg85Ser Uncertain significance ⚠ same condition
DACT1 p.Gly560Cys Uncertain significance ⚠ same condition
DACT1 p.Arg659= Likely benign same condition
DACT1 p.Asn336= Likely benign same condition

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-ser591ala (accessed [today's date]).

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