Is DACH1 p.Ser89Arg (c.267C>G) pathogenic?

DACH1 p.Ser89Arg (c.267C>G) is classified Uncertain significance in DACH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-08). AlphaMissense: likely benign (0.3387); Very rare (popmax 0.00142%, nfe).

How common is DACH1 p.Ser89Arg (c.267C>G) in the general population?

DACH1 p.Ser89Arg (c.267C>G) is very rare (popmax 0.00142%, nfe) (gnomAD).

What do computational predictors say about DACH1 p.Ser89Arg (c.267C>G)?

AlphaMissense predicts likely benign (score 0.3387) — an in-silico prediction, not a clinical call.

DACH1 p.Ser89Arg

c.267C>G · VCV3499541

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3387 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00142%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3387	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -11.03	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.21	GERP -2.6, phastCons 0.003
Regional constraint	o/e 0.99	unconstrained · MANE · 621 bp · p 0.83 · regional, not allelic
Overall
CADD	8.884	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 0.00142% European (non-Finnish) · 14/983,362 alleles

Filtering AF 0.000826% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000646%

Overall 0.00123% 15/1,222,876 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00226%	44,312
European (non-Finnish)grpmax	0.00142%	70,240

Remaining individuals 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: DACH1
Protein: p.Ser89Arg
Coding: c.267C>G
MANE Select: NM_080759
Type: single nucleotide variant
Location: chr13:71866503 (GRCh38)
Gene constraint: LOEUF 0.371 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 58.74 · 1 PDB
Residue 89: the 'disordered' 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-ser89arg (accessed [today's date]).

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