Is DACT1 p.Ala427Val (c.1280C>T) pathogenic?

DACT1 p.Ala427Val (c.1280C>T) is classified Benign in DACT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-07-30). AlphaMissense: likely benign (0.0786); Common (popmax 35.6%, sas) — too common for a highly-penetrant pathogenic allele; Associated with Townes-Brocks syndrome 2.

What condition is associated with DACT1 p.Ala427Val (c.1280C>T)?

DACT1 p.Ala427Val (c.1280C>T) is associated with Townes-Brocks syndrome 2 (ClinVar).

What do computational predictors say about DACT1 p.Ala427Val (c.1280C>T)?

AlphaMissense predicts likely benign (score 0.0786) — an in-silico prediction, not a clinical call.

DACT1 p.Ala427Val

Q: How common is DACT1 p.Ala427Val (c.1280C>T) in the general population?

DACT1 p.Ala427Val (c.1280C>T) is common (popmax 35.6%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1280C>T · rs17832998 · VCV1255448

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0786 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 35.6%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Townes-Brocks syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0786	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -6.47	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 -0.34	GERP -0.1
Regional constraint	o/e 1.10	unconstrained · MANE · 8,733 bp · p 0.0021 · regional, not allelic
Overall
CADD	6.576	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 A464V vs ClinVar A427V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 35.6% South Asian · 32,416/91,068 alleles

Filtering AF 35.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 35.1%

Overall 30.2% 487,042/1,613,906 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	40.8%	2
South Asiangrpmax	35.6%	3
Middle Eastern	33.4%	3
European (non-Finnish)	31.4%	3
Remaining individualsnot grpmax-eligible	30.6%	3
Ashkenazi Jewishnot grpmax-eligible	27.2%	4
African / African-American	26.1%	4
East Asian	23.3%	4
Finnishnot grpmax-eligible	23.1%	4
Admixed American	16.9%	6

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala427Val
Coding: c.1280C>T
MANE Select: NM_001079520
dbSNP: rs17832998
Type: single nucleotide variant
Location: chr14:58646014 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 50.95
Residue 427: 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.Glu451Asp Uncertain significance ★★ ⚠ 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
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-ala427val (accessed [today's date]).

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