Is HDAC4 p.Arg189= (c.567G>A) pathogenic?

HDAC4 p.Arg189= (c.567G>A) is classified Likely benign in HDAC4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-03-01). Ultra-rare (popmax 0.082%, nfe).

How common is HDAC4 p.Arg189= (c.567G>A) in the general population?

HDAC4 p.Arg189= (c.567G>A) is ultra-rare (popmax 0.082%, nfe) (gnomAD).

HDAC4 p.Arg189=

c.567G>A · rs141942329 · VCV282939

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.082%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.6	GERP -3.9
Overall
CADD	4.932	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.082% European (non-Finnish) · 968/1,180,024 alleles

Filtering AF 0.0777% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.076%

Overall 0.0711% 1,148/1,614,180 alleles · ultra-rare exomes 1,025/1,461,854 · genomes 123/152,326 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.114%	877
European (non-Finnish)grpmax	0.082%	1,219
Admixed American	0.0716%	1,396
Remaining individualsnot grpmax-eligible	0.0512%	1,953
South Asian	0.0285%	3,503
Middle Eastern	0.0165%	6,052
African / African-American	0.00533%	18,764
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604

Finnish 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: HDAC4
Protein: p.Arg189=
Coding: c.567G>A
MANE Select: NM_001378414
dbSNP: rs141942329
Type: single nucleotide variant
Location: chr2:239163847 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.67 · 19 PDB
Residue 189: the 'interaction with mef2a' region

Full HDAC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HDAC4 p.Arg189Trp Likely benign ★ ⚠ same residue
HDAC4 p.Pro248Leu Pathogenic ★★ same type
HDAC4 p.Thr244Lys Pathogenic/Likely pathogenic ★★ same type
HDAC4 c.865+8G>A Uncertain significance ★★ same type
HDAC4 p.Ala445Thr Uncertain significance ★★ ⚠ same type
HDAC4 p.Ala620Thr Uncertain significance ★★ ⚠ same type
HDAC4 p.Ala91Thr Uncertain significance ★★ ⚠ same type
HDAC4 p.Arg132Trp 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/hdac4-p-arg189 (accessed [today's date]).

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