Is DACT2 p.Ser667Leu (c.2000C>T) pathogenic?

DACT2 p.Ser667Leu (c.2000C>T) is classified Uncertain significance in DACT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.0977); Very rare (popmax 0.00245%, eas).

How common is DACT2 p.Ser667Leu (c.2000C>T) in the general population?

DACT2 p.Ser667Leu (c.2000C>T) is very rare (popmax 0.00245%, eas) (gnomAD).

What do computational predictors say about DACT2 p.Ser667Leu (c.2000C>T)?

AlphaMissense predicts likely benign (score 0.0977) — an in-silico prediction, not a clinical call.

DACT2 p.Ser667Leu

c.2000C>T · VCV4237438

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00245%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0977	likely benign
REVEL	0.357	indeterminate
SaProt	LLR -6.63	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 1.7, phastCons 0.042
Regional constraint	o/e 0.99	unconstrained · MANE · 12 kb · p 0.68 · regional, not allelic
Overall
CADD	22.3	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 0.00245% East Asian · 1/40,894 alleles

Filtering AF 0.0015% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00126%

Overall 0.00187% 29/1,547,336 alleles · very rare exomes 27/1,395,180 · genomes 2/152,156 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00245%	40,894
European (non-Finnish)	0.00218%	45,874
Admixed American	0.00196%	50,986
Remaining individualsnot grpmax-eligible	0.00167%	60,056
South Asian	0.00119%	84,048

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: DACT2
Protein: p.Ser667Leu
Coding: c.2000C>T
MANE Select: NM_214462
Type: single nucleotide variant
Location: chr6:168307757 (GRCh38)
Gene constraint: LOEUF 1.469 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.81
Residue 667: the 'disordered' region

Full DACT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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DACT2 p.Ala239Thr Uncertain significance ★ ⚠ same type
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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/dact2-p-ser667leu (accessed [today's date]).

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