Is DACH2 p.Pro421Ser (c.1261C>T) pathogenic?

DACH2 p.Pro421Ser (c.1261C>T) is classified Benign in DACH2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2014-10-31). AlphaMissense: likely benign (0.1688); Ultra-rare (popmax 0.071%, afr); Associated with Abnormality of neuronal migration.

What condition is associated with DACH2 p.Pro421Ser (c.1261C>T)?

DACH2 p.Pro421Ser (c.1261C>T) is associated with Abnormality of neuronal migration (ClinVar).

How common is DACH2 p.Pro421Ser (c.1261C>T) in the general population?

DACH2 p.Pro421Ser (c.1261C>T) is ultra-rare (popmax 0.071%, afr) (gnomAD).

What do computational predictors say about DACH2 p.Pro421Ser (c.1261C>T)?

AlphaMissense predicts likely benign (score 0.1688) — an in-silico prediction, not a clinical call.

DACH2 p.Pro421Ser

c.1261C>T · rs765715387 · VCV208891

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1688 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.071%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Abnormality of neuronal migration

Computational evidence

Protein change
AlphaMissense	0.1688	likely benign
REVEL	0.312	indeterminate
SaProt	LLR -7.14	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 0.65, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 455 kb · p 0.12 · regional, not allelic
Overall
CADD	20.8	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 0.071% African / African-American · 40/56,321 alleles

Filtering AF 0.0535% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0475%

Overall 0.00418% 50/1,195,532 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.071%	1,408
East Asian	0.015%	6,653
Remaining individualsnot grpmax-eligible	0.00639%	15,661
Admixed American	0.00231%	43,383
European (non-Finnish)	0.000112%	889,134

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.Pro421Ser
Coding: c.1261C>T
MANE Select: NM_053281
dbSNP: rs765715387
Type: single nucleotide variant
Location: chrX:86812876 (GRCh38)
Structure: AlphaFold pLDDT 62.69

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

Disease context

Abnormality of neuronal migration — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-pro421ser (accessed [today's date]).

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