Is DACT3 p.Arg413Cys (c.1237C>T) pathogenic?

DACT3 p.Arg413Cys (c.1237C>T) is classified Uncertain significance in DACT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-08). AlphaMissense: likely pathogenic (0.6829); Very rare (popmax 0.00488%, sas).

How common is DACT3 p.Arg413Cys (c.1237C>T) in the general population?

DACT3 p.Arg413Cys (c.1237C>T) is very rare (popmax 0.00488%, sas) (gnomAD).

What do computational predictors say about DACT3 p.Arg413Cys (c.1237C>T)?

AlphaMissense predicts likely pathogenic (score 0.6829) — an in-silico prediction, not a clinical call.

DACT3 p.Arg413Cys

c.1237C>T · VCV3838176

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6829 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00488%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6829	likely pathogenic
REVEL	0.139	moderately benign-leaning
SaProt	LLR -8.37	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP -2.5, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,201 bp · p 0.027 · regional, not allelic
Overall
CADD	23.8	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 0.00488% South Asian · 2/40,982 alleles

Filtering AF 0.000809% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000303%

Overall 0.000395% 5/1,267,356 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00488%	20,491
Remaining individualsnot grpmax-eligible	0.00437%	22,899
European (non-Finnish)	9.91e-05%	1,008,614

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: DACT3
Protein: p.Arg413Cys
Coding: c.1237C>T
MANE Select: NM_145056
Type: single nucleotide variant
Location: chr19:46649135 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI 0.65 (gnomAD)
Structure: AlphaFold pLDDT 53.51
Residue 413: the 'disordered' region

Full DACT3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DACT3 p.Arg413His Uncertain significance ★ ⚠ same residue
DACT3 p.Ala179Pro Uncertain significance ★ ⚠ same type
DACT3 p.Ala181Ser Uncertain significance ★ ⚠ same type
DACT3 p.Ala181Thr Uncertain significance ★ ⚠ same type
DACT3 p.Ala194Thr Uncertain significance ★ ⚠ same type
DACT3 p.Ala299Gly Uncertain significance ★ ⚠ same type
DACT3 p.Ala318Ser Uncertain significance ★ ⚠ same type
DACT3 p.Ala338Pro 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/dact3-p-arg413cys (accessed [today's date]).

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