Is DACT1 p.Gly660Ser (c.1978G>A) pathogenic?

DACT1 p.Gly660Ser (c.1978G>A) is classified Benign in DACT1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-27). AlphaMissense: likely benign (0.0728); Common (popmax 38.3%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about DACT1 p.Gly660Ser (c.1978G>A)?

AlphaMissense predicts likely benign (score 0.0728) — an in-silico prediction, not a clinical call.

DACT1 p.Gly660Ser

Q: How common is DACT1 p.Gly660Ser (c.1978G>A) in the general population?

DACT1 p.Gly660Ser (c.1978G>A) is common (popmax 38.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1978G>A · rs698025 · VCV1257885

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0728 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 38.3%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0728	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -5.38	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 2.2	GERP -2.2, phastCons 0.016
Regional constraint	o/e 1.10	unconstrained · MANE · 8,733 bp · p 0.0021 · regional, not allelic
Overall
CADD	9.785	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM G697S vs ClinVar G660S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 38.3% African / African-American · 28,677/74,946 alleles

Filtering AF 37.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 37.7%

Overall 20.2% 326,378/1,612,976 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	38.3%	3
Admixed American	34.2%	3
Middle Eastern	28%	4
Ashkenazi Jewishnot grpmax-eligible	26.2%	4
Remaining individualsnot grpmax-eligible	21.5%	5
South Asian	20.8%	5
European (non-Finnish)	18.5%	5
Finnishnot grpmax-eligible	17.9%	6
East Asian	13.4%	7
Amishnot grpmax-eligible	12.5%	8

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.Gly660Ser
Coding: c.1978G>A
MANE Select: NM_001079520
dbSNP: rs698025
Type: single nucleotide variant
Location: chr14:58646712 (GRCh38)
Gene constraint: LOEUF 0.703 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 50.95
Residue 660: 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.Gly660Ala Uncertain significance ★ ⚠ same residue
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

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-gly660ser (accessed [today's date]).

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