Is DACH1 p.Pro306Leu (c.917C>T) pathogenic?

DACH1 p.Pro306Leu (c.917C>T) is classified Uncertain significance in DACH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-31). AlphaMissense: likely pathogenic (0.691); Very rare (popmax 0.0022%, sas).

How common is DACH1 p.Pro306Leu (c.917C>T) in the general population?

DACH1 p.Pro306Leu (c.917C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about DACH1 p.Pro306Leu (c.917C>T)?

AlphaMissense predicts likely pathogenic (score 0.691) — an in-silico prediction, not a clinical call.

DACH1 p.Pro306Leu

c.917C>T · VCV3838137

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.691 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.691	likely pathogenic
REVEL	0.576	indeterminate
SaProt	LLR -7.58	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 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 425 kb · p 0.0017 · regional, not allelic
Overall
CADD	34.0	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 0.0022% South Asian · 2/91,082 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000372% 6/1,613,824 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,541
Remaining individualsnot grpmax-eligible	0.0016%	62,470
European (non-Finnish)	0.000254%	393,297

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: DACH1
Protein: p.Pro306Leu
Coding: c.917C>T
MANE Select: NM_080759
Type: single nucleotide variant
Location: chr13:71681842 (GRCh38)
Gene constraint: LOEUF 0.371 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 58.74 · 1 PDB
Residue 306: the 'interaction with six6 and hdac3' region

Full DACH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DACH1 p.Val375= Benign ★★ same type
DACH1 c.1722+6C>T Conflicting classifications of pathogenicity ★ same type
DACH1 p.Ala109Val Uncertain significance ★ ⚠ same type
DACH1 p.Ala36Glu Uncertain significance ★ ⚠ same type
DACH1 p.Ala36Val Uncertain significance ★ ⚠ same type
DACH1 p.Ala418Thr Uncertain significance ★ ⚠ same type
DACH1 p.Ala533Thr Uncertain significance ★ ⚠ same type
DACH1 p.Ala586Thr 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/dach1-p-pro306leu (accessed [today's date]).

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