Is DACT1 p.Thr568Met (c.1703C>T) pathogenic?

DACT1 p.Thr568Met (c.1703C>T) is classified Uncertain significance in DACT1 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.0928); Very rare (popmax 0.00227%, eas); Associated with Townes-Brocks syndrome 2.

What condition is associated with DACT1 p.Thr568Met (c.1703C>T)?

DACT1 p.Thr568Met (c.1703C>T) is associated with Townes-Brocks syndrome 2 (ClinVar).

How common is DACT1 p.Thr568Met (c.1703C>T) in the general population?

DACT1 p.Thr568Met (c.1703C>T) is very rare (popmax 0.00227%, eas) (gnomAD).

What do computational predictors say about DACT1 p.Thr568Met (c.1703C>T)?

AlphaMissense predicts likely benign (score 0.0928) — an in-silico prediction, not a clinical call.

DACT1 p.Thr568Met

c.1703C>T · rs1430682606 · VCV3242040

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0928 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00227%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Townes-Brocks syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0928	likely benign
REVEL	0.154	moderately benign-leaning
SaProt	LLR -8.11	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 1.1	GERP -4.5, phastCons 0.001
Regional constraint	o/e 1.10	unconstrained · MANE · 8,733 bp · p 0.0021 · regional, not allelic
Overall
CADD	12.32	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 T605M vs ClinVar T568M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00227% East Asian · 1/44,070 alleles

Overall 0.000657% 1/152,300 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: DACT1
Protein: p.Thr568Met
Coding: c.1703C>T
MANE Select: NM_001079520
dbSNP: rs1430682606
Type: single nucleotide variant
Location: chr14:58646437 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 50.95
Residue 568: a UniProt-annotated variant site (in tbs2; the mutant protein is stable and expressed)

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

Disease context

Townes-Brocks syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DACT1 p.Glu451Asp Uncertain significance ★★ ⚠ same condition
DACT1 p.Ala427Val Benign ★★ same condition
DACT1 p.Glu257Lys Benign/Likely benign ★★ same condition
DACT1 p.Leu90= Benign ★★ same condition
DACT1 p.Gln310His Conflicting classifications of pathogenicity ★ ⚠ same condition
DACT1 p.Glu708Lys Uncertain significance ★ ⚠ same condition
DACT1 p.Gly744Ser Uncertain significance ★ ⚠ same condition
DACT1 p.Phe376Leu Uncertain significance ★ ⚠ 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-thr568met (accessed [today's date]).

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