Is DACT1 p.Arg85Ser (c.253C>A) pathogenic?

DACT1 p.Arg85Ser (c.253C>A) is classified Uncertain significance in DACT1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-04-28). AlphaMissense: likely benign (0.2691); Very rare (popmax 9.55e-05%, nfe); Associated with DACT1-related disorder.

What condition is associated with DACT1 p.Arg85Ser (c.253C>A)?

DACT1 p.Arg85Ser (c.253C>A) is associated with DACT1-related disorder (ClinVar).

How common is DACT1 p.Arg85Ser (c.253C>A) in the general population?

DACT1 p.Arg85Ser (c.253C>A) is very rare (popmax 9.55e-05%, nfe) (gnomAD).

What do computational predictors say about DACT1 p.Arg85Ser (c.253C>A)?

AlphaMissense predicts likely benign (score 0.2691) — an in-silico prediction, not a clinical call.

DACT1 p.Arg85Ser

c.253C>A · VCV3344680

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2691 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.55e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DACT1-related disorder

Computational evidence

Protein change
AlphaMissense	0.2691	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -6.88	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 2.4	GERP 2, phastCons 0.99
Regional constraint	o/e 1.10	unconstrained · MANE · 8,733 bp · p 0.0021 · regional, not allelic
Overall
CADD	18.37	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 9.55e-05% European (non-Finnish) · 1/1,047,448 alleles

Overall 0.000657% 1/152,180 alleles · very rare

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.Arg85Ser
Coding: c.253C>A
MANE Select: NM_001079520
Type: single nucleotide variant
Location: chr14:58638455 (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

DACT1-related disorder

Similar variants

DACT1 p.Arg85Gly Uncertain significance ★ ⚠ same residue
DACT1 p.Ala9Pro Uncertain significance ★ ⚠ same condition
DACT1 p.His426Arg Uncertain significance ★ ⚠ same condition
DACT1 p.Pro295Ala Uncertain significance ★ ⚠ same condition
DACT1 p.Ala677Ser Uncertain significance ⚠ same condition
DACT1 p.Gly560Cys Uncertain significance ⚠ same condition
DACT1 p.Arg659= Likely benign same condition
DACT1 p.Asn336= Likely benign 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-arg85ser (accessed [today's date]).

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