Is DACT1 p.Gln42Lys (c.124C>A) pathogenic?

DACT1 p.Gln42Lys (c.124C>A) is classified Uncertain significance in DACT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-07). AlphaMissense: likely benign (0.2619); Ultra-rare (popmax 0.0534%, nfe).

How common is DACT1 p.Gln42Lys (c.124C>A) in the general population?

DACT1 p.Gln42Lys (c.124C>A) is ultra-rare (popmax 0.0534%, nfe) (gnomAD).

What do computational predictors say about DACT1 p.Gln42Lys (c.124C>A)?

AlphaMissense predicts likely benign (score 0.2619) — an in-silico prediction, not a clinical call.

DACT1 p.Gln42Lys

c.124C>A · rs537744325 · VCV2408257

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2619 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0534%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2619	likely benign
REVEL	0.142	moderately benign-leaning
SaProt	LLR -6.39	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 7.2	GERP 1.2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 156 bp · p 0.72 · regional, not allelic
Overall
CADD	23.5	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0534% European (non-Finnish) · 556/1,041,086 alleles

Filtering AF 0.0496% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0482%

Overall 0.0433% 572/1,321,472 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0534%	1,872
Remaining individualsnot grpmax-eligible	0.0202%	4,950
Admixed American	0.0081%	12,349
African / African-American	0.00462%	21,650
Finnishnot grpmax-eligible	0.00265%	37,724

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.Gln42Lys
Coding: c.124C>A
MANE Select: NM_001079520
dbSNP: rs537744325
Type: single nucleotide variant
Location: chr14:58638326 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 50.95
Residue 42: the 'disordered' region

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-gln42lys (accessed [today's date]).

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