Is DACT3 p.Arg417Gly (c.1249A>G) pathogenic?

DACT3 p.Arg417Gly (c.1249A>G) is classified Uncertain significance in DACT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: ambiguous (0.4444); Very rare (popmax 0.00315%, nfe).

How common is DACT3 p.Arg417Gly (c.1249A>G) in the general population?

DACT3 p.Arg417Gly (c.1249A>G) is very rare (popmax 0.00315%, nfe) (gnomAD).

What do computational predictors say about DACT3 p.Arg417Gly (c.1249A>G)?

AlphaMissense predicts ambiguous (score 0.4444) — an in-silico prediction, not a clinical call.

DACT3 p.Arg417Gly

c.1249A>G · VCV4237460

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4444 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00315%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4444	ambiguous
REVEL	0.221	benign-leaning
SaProt	LLR -6.43	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.056	GERP -2.4, phastCons 0.53
Regional constraint	o/e 1.09	unconstrained · MANE · 1,201 bp · p 0.027 · regional, not allelic
Overall
CADD	20.3	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 0.00315% European (non-Finnish) · 32/1,014,556 alleles

Filtering AF 0.00228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00284% 32/1,127,956 alleles · very 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: DACT3
Protein: p.Arg417Gly
Coding: c.1249A>G
MANE Select: NM_145056
Type: single nucleotide variant
Location: chr19:46649123 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI 0.65 (gnomAD)
Structure: AlphaFold pLDDT 53.51
Residue 417: the 'disordered' region

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

Similar variants

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
DACT3 p.Ala363Val 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-arg417gly (accessed [today's date]).

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