Is DACH2 p.Ala219Val (c.656C>T) pathogenic?

DACH2 p.Ala219Val (c.656C>T) is classified Conflicting classifications of pathogenicity in DACH2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-03-01). AlphaMissense: likely benign (0.3256); Ultra-rare (popmax 0.0247%, nfe).

How common is DACH2 p.Ala219Val (c.656C>T) in the general population?

DACH2 p.Ala219Val (c.656C>T) is ultra-rare (popmax 0.0247%, nfe) (gnomAD).

What do computational predictors say about DACH2 p.Ala219Val (c.656C>T)?

AlphaMissense predicts likely benign (score 0.3256) — an in-silico prediction, not a clinical call.

DACH2 p.Ala219Val

c.656C>T · rs151230279 · VCV2661008

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3256 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0247%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3256	likely benign
REVEL	0.518	indeterminate
SaProt	LLR -9.15	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 4.4	GERP 1.4, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 455 kb · p 0.12 · regional, not allelic
Overall
CADD	24.8	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 0.0247% European (non-Finnish) · 220/891,935 alleles

Filtering AF 0.022% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0209%

Overall 0.0365% 439/1,203,718 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.621%	161
Finnishnot grpmax-eligible	0.119%	843
Remaining individualsnot grpmax-eligible	0.0528%	1,893
European (non-Finnish)grpmax	0.0247%	4,054
Admixed American	0.00443%	22,563
South Asian	0.00179%	55,771

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala219Val
Coding: c.656C>T
MANE Select: NM_053281
dbSNP: rs151230279
Type: single nucleotide variant
Location: chrX:86651051 (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.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
DACH2 p.Ala440Thr 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-ala219val (accessed [today's date]).

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