Is DACT1 p.Pro84Leu (c.251C>T) pathogenic?

DACT1 p.Pro84Leu (c.251C>T) is classified Conflicting classifications of pathogenicity in DACT1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-02-20). AlphaMissense: likely benign (0.1558); Ultra-rare (popmax 0.0624%, amr).

How common is DACT1 p.Pro84Leu (c.251C>T) in the general population?

DACT1 p.Pro84Leu (c.251C>T) is ultra-rare (popmax 0.0624%, amr) (gnomAD).

What do computational predictors say about DACT1 p.Pro84Leu (c.251C>T)?

AlphaMissense predicts likely benign (score 0.1558) — an in-silico prediction, not a clinical call.

DACT1 p.Pro84Leu

c.251C>T · rs750573800 · VCV717461

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1558 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0624%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1558	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -6.98	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 0.59	GERP 0.15
Regional constraint	o/e 1.10	unconstrained · MANE · 8,733 bp · p 0.0021 · regional, not allelic
Overall
CADD	11.38	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0624% Admixed American · 20/32,068 alleles

Filtering AF 0.0413% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0346%

Overall 0.00429% 58/1,351,712 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0624%	1,603
Remaining individualsnot grpmax-eligible	0.01%	9,988
Ashkenazi Jewishnot grpmax-eligible	0.00513%	19,508
European (non-Finnish)	0.00286%	34,915
South Asian	0.00229%	43,642
African / African-American	0.00151%	66,434

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.Pro84Leu
Coding: c.251C>T
MANE Select: NM_001079520
dbSNP: rs750573800
Type: single nucleotide variant
Location: chr14:58638453 (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.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
DACT1 p.Glu49= Likely benign ★★ same type
DACT1 p.Gly660Ser 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-pro84leu (accessed [today's date]).

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