Is HDAC4 p.Arg535His (c.1604G>A) pathogenic?

HDAC4 p.Arg535His (c.1604G>A) is classified Uncertain significance in HDAC4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-29). AlphaMissense: likely benign (0.2147); Very rare (popmax 0.00678%, nfe); Associated with Inborn genetic diseases.

What condition is associated with HDAC4 p.Arg535His (c.1604G>A)?

HDAC4 p.Arg535His (c.1604G>A) is associated with Inborn genetic diseases, neurodevelopmental disorder with central hypotonia and dysmorphic facies (ClinVar).

How common is HDAC4 p.Arg535His (c.1604G>A) in the general population?

HDAC4 p.Arg535His (c.1604G>A) is very rare (popmax 0.00678%, nfe) (gnomAD).

What do computational predictors say about HDAC4 p.Arg535His (c.1604G>A)?

AlphaMissense predicts likely benign (score 0.2147) — an in-silico prediction, not a clinical call.

HDAC4 p.Arg535His

c.1604G>A · rs553454254 · VCV2432394

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2147 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00678%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2147	likely benign
REVEL	0.149	moderately benign-leaning
SaProt	LLR -8.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP -1.4, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 15 kb · p 0.31 · regional, not allelic
Overall
CADD	28.7	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R530H vs ClinVar R535H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00678% European (non-Finnish) · 80/1,179,682 alleles

Filtering AF 0.00555% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.00533% 86/1,612,616 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00678%	14,746
African / African-American	0.004%	24,979
East Asian	0.00223%	44,888
South Asian	0.0022%	45,522

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.Arg535His
Coding: c.1604G>A
MANE Select: NM_001378414
dbSNP: rs553454254
Type: single nucleotide variant
Location: chr2:239115240 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.67 · 19 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neurodevelopmental disorder with central hypotonia and dysmorphic facies

Similar variants

HDAC4 p.Arg535Cys Uncertain significance ★ ⚠ same residue
HDAC4 p.Pro248Leu Pathogenic ★★ same condition
HDAC4 p.Thr244Lys Pathogenic/Likely pathogenic ★★ same condition
HDAC4 p.Ala445Thr Uncertain significance ★★ ⚠ same condition
HDAC4 p.Ala620Thr Uncertain significance ★★ ⚠ same condition
HDAC4 p.Ala91Thr Uncertain significance ★★ ⚠ same condition
HDAC4 p.Arg132Trp Uncertain significance ★★ ⚠ same condition
HDAC4 p.Arg13Gln Uncertain significance ★★ ⚠ same condition

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-arg535his (accessed [today's date]).

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