Is DACT1 p.Val339Leu (c.1015G>C) pathogenic?

DACT1 p.Val339Leu (c.1015G>C) is classified Uncertain significance in DACT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.1242); Ultra-rare (popmax 0.0325%, nfe).

How common is DACT1 p.Val339Leu (c.1015G>C) in the general population?

DACT1 p.Val339Leu (c.1015G>C) is ultra-rare (popmax 0.0325%, nfe) (gnomAD).

What do computational predictors say about DACT1 p.Val339Leu (c.1015G>C)?

AlphaMissense predicts likely benign (score 0.1242) — an in-silico prediction, not a clinical call.

DACT1 p.Val339Leu

c.1015G>C · rs377732832 · VCV2364029

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1242 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0325%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1242	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -6.09	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 0.48	GERP -2.3, phastCons 0.023
Regional constraint	o/e 1.10	unconstrained · MANE · 8,733 bp · p 0.0021 · regional, not allelic
Overall
CADD	2.62	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V376L vs ClinVar V339L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0325% European (non-Finnish) · 384/1,180,052 alleles

Filtering AF 0.0298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0288%

Overall 0.0247% 398/1,614,140 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0325%	3,073
Remaining individualsnot grpmax-eligible	0.016%	6,249
African / African-American	0.00267%	37,479
Admixed American	0.00167%	60,010
Finnishnot grpmax-eligible	0.00156%	64,048

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.Val339Leu
Coding: c.1015G>C
MANE Select: NM_001079520
dbSNP: rs377732832
Type: single nucleotide variant
Location: chr14:58645749 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 50.95

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

Similar variants

DACT1 p.Val339Gly Uncertain significance ★ ⚠ same residue
DACT1 p.Val339= Likely benign same residue
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

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-val339leu (accessed [today's date]).

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