Is DACH2 p.Pro445Ser (c.1333C>T) pathogenic?

DACH2 p.Pro445Ser (c.1333C>T) is classified Uncertain significance in DACH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-12). AlphaMissense: likely benign (0.1446); Very rare (popmax 0.000112%, nfe).

How common is DACH2 p.Pro445Ser (c.1333C>T) in the general population?

DACH2 p.Pro445Ser (c.1333C>T) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about DACH2 p.Pro445Ser (c.1333C>T)?

AlphaMissense predicts likely benign (score 0.1446) — an in-silico prediction, not a clinical call.

DACH2 p.Pro445Ser

c.1333C>T · rs1303564495 · VCV2282892

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1446 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1446	likely benign
REVEL	0.487	indeterminate
SaProt	LLR -10.56	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 0.76, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 455 kb · p 0.12 · regional, not allelic
Overall
CADD	21.0	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 0.000112% European (non-Finnish) · 1/893,638 alleles

Overall 9.13e-05% 1/1,095,403 alleles · very rare

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.Pro445Ser
Coding: c.1333C>T
MANE Select: NM_053281
dbSNP: rs1303564495
Type: single nucleotide variant
Location: chrX:86812948 (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-pro445ser (accessed [today's date]).

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