Is DACH2 p.Ala440Thr (c.1318G>A) pathogenic?

DACH2 p.Ala440Thr (c.1318G>A) is classified Uncertain significance in DACH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely benign (0.075); Ultra-rare (popmax 0.0725%, amr).

How common is DACH2 p.Ala440Thr (c.1318G>A) in the general population?

DACH2 p.Ala440Thr (c.1318G>A) is ultra-rare (popmax 0.0725%, amr) (gnomAD).

What do computational predictors say about DACH2 p.Ala440Thr (c.1318G>A)?

AlphaMissense predicts likely benign (score 0.075) — an in-silico prediction, not a clinical call.

DACH2 p.Ala440Thr

c.1318G>A · rs748352318 · VCV2515473

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.075 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0725%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.075	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	LLR -6.36	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 0.41	GERP -3.1, phastCons 0.096
Regional constraint	o/e 1.09	unconstrained · MANE · 455 kb · p 0.12 · regional, not allelic
Overall
CADD	12.66	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 0.0725% Admixed American · 33/45,503 alleles

Filtering AF 0.053% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0463%

Overall 0.00589% 71/1,205,172 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0725%	1,379
Remaining individualsnot grpmax-eligible	0.00633%	15,808
East Asian	0.00594%	16,822
European (non-Finnish)	0.00348%	28,766
Finnishnot grpmax-eligible	0.00215%	46,446
South Asian	0.00177%	56,408

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: DACH2
Protein: p.Ala440Thr
Coding: c.1318G>A
MANE Select: NM_053281
dbSNP: rs748352318
Type: single nucleotide variant
Location: chrX:86812933 (GRCh38)
Structure: AlphaFold pLDDT 62.69

Full DACH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DACH2 p.Arg539His Uncertain significance ★★ ⚠ same type
DACH2 p.Ala219Val Conflicting classifications of pathogenicity ★ ⚠ same type
DACH2 p.Ala221Asp Uncertain significance ★ ⚠ same type
DACH2 p.Ala221Ser Uncertain significance ★ ⚠ same type
DACH2 p.Ala223Val Uncertain significance ★ ⚠ same type
DACH2 p.Ala285Glu Uncertain significance ★ ⚠ same type
DACH2 p.Ala296Val Uncertain significance ★ ⚠ same type
DACH2 p.Ala362Gly 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/dach2-p-ala440thr (accessed [today's date]).

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