Is DACT1 p.Pro673Ser (c.2017C>T) pathogenic?

DACT1 p.Pro673Ser (c.2017C>T) is classified Uncertain significance in DACT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-16). AlphaMissense: likely benign (0.0679); Very rare (popmax 0.00466%, nfe).

How common is DACT1 p.Pro673Ser (c.2017C>T) in the general population?

DACT1 p.Pro673Ser (c.2017C>T) is very rare (popmax 0.00466%, nfe) (gnomAD).

What do computational predictors say about DACT1 p.Pro673Ser (c.2017C>T)?

AlphaMissense predicts likely benign (score 0.0679) — an in-silico prediction, not a clinical call.

DACT1 p.Pro673Ser

c.2017C>T · rs756585155 · VCV2486467

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0679 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00466%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0679	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -7.11	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 1.4	GERP -4.4, phastCons 0.98
Regional constraint	o/e 1.10	unconstrained · MANE · 8,733 bp · p 0.0021 · regional, not allelic
Overall
CADD	3.359	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P710S vs ClinVar P673S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00466% European (non-Finnish) · 55/1,180,030 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00329%

Overall 0.00353% 57/1,613,956 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00466%	21,455
Remaining individualsnot grpmax-eligible	0.0016%	62,506
South Asian	0.0011%	91,088

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.Pro673Ser
Coding: c.2017C>T
MANE Select: NM_001079520
dbSNP: rs756585155
Type: single nucleotide variant
Location: chr14:58646751 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 50.95
Residue 673: 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

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-pro673ser (accessed [today's date]).

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