Is DACT3 p.Ser186Phe (c.557C>T) pathogenic?

DACT3 p.Ser186Phe (c.557C>T) is classified Uncertain significance in DACT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-19). AlphaMissense: likely pathogenic (0.9616); Very rare (popmax 0.00925%, amr).

How common is DACT3 p.Ser186Phe (c.557C>T) in the general population?

DACT3 p.Ser186Phe (c.557C>T) is very rare (popmax 0.00925%, amr) (gnomAD).

What do computational predictors say about DACT3 p.Ser186Phe (c.557C>T)?

AlphaMissense predicts likely pathogenic (score 0.9616) — an in-silico prediction, not a clinical call.

DACT3 p.Ser186Phe

c.557C>T · VCV3838171

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9616 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00925%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9616	likely pathogenic · top 9% in DACT3
REVEL	0.413	indeterminate
SaProt	LLR -10.00	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.27, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 11 kb · p 4.5e-05 · regional, not allelic
Overall
CADD	29.0	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 0.00925% Admixed American · 3/32,426 alleles

Filtering AF 0.00245% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00128%

Overall 0.00451% 64/1,418,720 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.186%	539
Remaining individualsnot grpmax-eligible	0.0111%	8,972
Admixed Americangrpmax	0.00925%	10,809
European (non-Finnish)	0.000824%	121,301

Ashkenazi Jewish 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: DACT3
Protein: p.Ser186Phe
Coding: c.557C>T
MANE Select: NM_145056
Type: single nucleotide variant
Location: chr19:46649815 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI 0.65 (gnomAD)
Structure: AlphaFold pLDDT 53.51
Residue 186: the 'disordered' region

Full DACT3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DACT3 p.Ala179Pro Uncertain significance ★ ⚠ same type
DACT3 p.Ala181Ser Uncertain significance ★ ⚠ same type
DACT3 p.Ala181Thr Uncertain significance ★ ⚠ same type
DACT3 p.Ala194Thr Uncertain significance ★ ⚠ same type
DACT3 p.Ala299Gly Uncertain significance ★ ⚠ same type
DACT3 p.Ala318Ser Uncertain significance ★ ⚠ same type
DACT3 p.Ala338Pro Uncertain significance ★ ⚠ same type
DACT3 p.Ala363Val Uncertain significance ★ ⚠ 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/dact3-p-ser186phe (accessed [today's date]).

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