Is DACT1 p.Leu90= (c.268C>T) pathogenic?

DACT1 p.Leu90= (c.268C>T) is classified Benign in DACT1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-27). Common (popmax 67.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Townes-Brocks syndrome 2.

What condition is associated with DACT1 p.Leu90= (c.268C>T)?

DACT1 p.Leu90= (c.268C>T) is associated with Townes-Brocks syndrome 2 (ClinVar).

DACT1 p.Leu90=

Q: How common is DACT1 p.Leu90= (c.268C>T) in the general population?

DACT1 p.Leu90= (c.268C>T) is common (popmax 67.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.268C>T · rs2003021 · VCV1255447

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 67.1%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Townes-Brocks syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP -1.8, phastCons 1
Overall
CADD	9.218	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 67.1% African / African-American · 44,738/66,660 alleles

Filtering AF 66.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 66.4%

Overall 52.9% 717,632/1,356,664 alleles · common exomes 632,462/1,204,564 · genomes 85,170/152,100 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	67.1%	1
Middle Eastern	62.6%	2
South Asian	57.6%	2
Remaining individualsnot grpmax-eligible	54.5%	2
Admixed American	54.4%	2
Amishnot grpmax-eligible	53.3%	2
European (non-Finnish)	52.5%	2
Ashkenazi Jewishnot grpmax-eligible	52.3%	2
Finnishnot grpmax-eligible	46%	2
East Asian	36.4%	3

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.Leu90=
Coding: c.268C>T
MANE Select: NM_001079520
dbSNP: rs2003021
Type: single nucleotide variant
Location: chr14:58638470 (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

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.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
DACT1 p.Thr330Lys Conflicting classifications of pathogenicity ★ ⚠ 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-leu90 (accessed [today's date]).

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