Is DACT1 p.Leu554Phe (c.1660C>T) pathogenic?

DACT1 p.Leu554Phe (c.1660C>T) is classified Pathogenic in DACT1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-03-09). AlphaMissense: likely benign (0.063); Ultra-rare (popmax 0.0742%, afr); Associated with Townes-Brocks syndrome 2.

What condition is associated with DACT1 p.Leu554Phe (c.1660C>T)?

DACT1 p.Leu554Phe (c.1660C>T) is associated with Townes-Brocks syndrome 2 (ClinVar).

How common is DACT1 p.Leu554Phe (c.1660C>T) in the general population?

DACT1 p.Leu554Phe (c.1660C>T) is ultra-rare (popmax 0.0742%, afr) (gnomAD).

What do computational predictors say about DACT1 p.Leu554Phe (c.1660C>T)?

AlphaMissense predicts likely benign (score 0.063) — an in-silico prediction, not a clinical call.

DACT1 p.Leu554Phe

c.1660C>T · rs369268433 · VCV2443965

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.063 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0742%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Townes-Brocks syndrome 2

Computational evidence

Protein change
AlphaMissense	0.063	likely benign ⚠ discordant with ClinVar
REVEL	0.052	moderately benign-leaning
SaProt	LLR -7.74	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 0.61	GERP -0.4
Regional constraint	o/e 1.10	unconstrained · MANE · 8,733 bp · p 0.0021 · regional, not allelic
Overall
CADD	15.01	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 L591F vs ClinVar L554F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0742% African / African-American · 55/74,078 alleles

Filtering AF 0.0585% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0529%

Overall 0.0053% 85/1,603,252 alleles · ultra-rare exomes 61/1,450,894 · genomes 24/152,358 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0742%	1,347
Remaining individualsnot grpmax-eligible	0.0306%	3,264
Middle Eastern	0.0166%	6,018
South Asian	0.00783%	12,772
Admixed American	0.00359%	27,855
European (non-Finnish)	8.49e-05%	1,177,334

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.Leu554Phe
Coding: c.1660C>T
MANE Select: NM_001079520
dbSNP: rs369268433
Type: single nucleotide variant
Location: chr14:58646394 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 50.95
Residue 591 UniProt numbering: 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

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

Similar variants

DACT1 p.Leu554= Likely benign ★ same residue
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

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-leu554phe (accessed [today's date]).

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