Is DACH2 p.Leu560Phe (c.1680A>C) pathogenic?

DACH2 p.Leu560Phe (c.1680A>C) is classified Uncertain significance in DACH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-09). AlphaMissense: likely benign (0.1549); Ultra-rare (popmax 0.086%, nfe).

How common is DACH2 p.Leu560Phe (c.1680A>C) in the general population?

DACH2 p.Leu560Phe (c.1680A>C) is ultra-rare (popmax 0.086%, nfe) (gnomAD).

What do computational predictors say about DACH2 p.Leu560Phe (c.1680A>C)?

AlphaMissense predicts likely benign (score 0.1549) — an in-silico prediction, not a clinical call.

DACH2 p.Leu560Phe

c.1680A>C · rs138579209 · VCV2287680

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1549 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.086%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1549	likely benign
REVEL	0.53	indeterminate
SaProt	LLR -7.46	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 2.4	GERP -4, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 455 kb · p 0.12 · regional, not allelic
Overall
CADD	21.9	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 0.086% European (non-Finnish) · 768/892,804 alleles

Filtering AF 0.0809% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0789%

Overall 0.0672% 809/1,204,685 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.086%	1,163
Remaining individualsnot grpmax-eligible	0.0422%	2,368
Admixed American	0.02%	4,994
South Asian	0.0108%	9,269
African / African-American	0.0105%	9,504

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.Leu560Phe
Coding: c.1680A>C
MANE Select: NM_053281
dbSNP: rs138579209
Type: single nucleotide variant
Location: chrX:86814830 (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-leu560phe (accessed [today's date]).

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