Is DACH2 p.Thr364Ile (c.1091C>T) pathogenic?

DACH2 p.Thr364Ile (c.1091C>T) is classified Uncertain significance in DACH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-27). AlphaMissense: likely benign (0.1666); Rare (popmax 0.135%, nfe).

How common is DACH2 p.Thr364Ile (c.1091C>T) in the general population?

DACH2 p.Thr364Ile (c.1091C>T) is rare (popmax 0.135%, nfe) (gnomAD).

What do computational predictors say about DACH2 p.Thr364Ile (c.1091C>T)?

AlphaMissense predicts likely benign (score 0.1666) — an in-silico prediction, not a clinical call.

DACH2 p.Thr364Ile

c.1091C>T · rs146840744 · VCV2366211

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1666 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.135%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1666	likely benign
REVEL	0.228	benign-leaning
SaProt	LLR -7.25	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 5.7	GERP 2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 455 kb · p 0.12 · regional, not allelic
Overall
CADD	22.5	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 0.135% European (non-Finnish) · 1,173/870,473 alleles

Filtering AF 0.128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.126%

Overall 0.103% 1,205/1,172,094 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.135%	742
Remaining individualsnot grpmax-eligible	0.0503%	1,988
African / African-American	0.0141%	7,070
Admixed American	0.00227%	44,053

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.Thr364Ile
Coding: c.1091C>T
MANE Select: NM_053281
dbSNP: rs146840744
Type: single nucleotide variant
Location: chrX:86714707 (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-thr364ile (accessed [today's date]).

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