Is HDAC4 p.Pro1087= (c.3261G>A) pathogenic?

HDAC4 p.Pro1087= (c.3261G>A) is classified Likely benign in HDAC4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-07-18). Ultra-rare (popmax 0.0164%, mid); Associated with HDAC4-related disorder.

What condition is associated with HDAC4 p.Pro1087= (c.3261G>A)?

HDAC4 p.Pro1087= (c.3261G>A) is associated with HDAC4-related disorder (ClinVar).

How common is HDAC4 p.Pro1087= (c.3261G>A) in the general population?

HDAC4 p.Pro1087= (c.3261G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

HDAC4 p.Pro1087=

c.3261G>A · VCV3353017

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

HDAC4-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.035	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5	GERP -1.5
Overall
CADD	10.01	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00161% 26/1,614,094 alleles · ultra-rare exomes 22/1,461,858 · genomes 4/152,236 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0048%	20,829
Admixed American	0.00333%	30,006
South Asian	0.00329%	30,363
African / African-American	0.00267%	37,472
European (non-Finnish)	0.00127%	78,669

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.Pro1087=
Coding: c.3261G>A
MANE Select: NM_001378414
Type: single nucleotide variant
Location: chr2:239053106 (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

HDAC4-related disorder

Similar variants

HDAC4 p.Thr244Lys Pathogenic/Likely pathogenic ★★ same condition
HDAC4 p.Met49Val Uncertain significance ★★ ⚠ same condition
HDAC4 p.Pro16Ala Uncertain significance ★★ ⚠ same condition
HDAC4 p.Arg709Leu Uncertain significance ★ ⚠ same condition
HDAC4 p.Gln382Arg Uncertain significance ★ ⚠ same condition
HDAC4 p.Leu600Val Uncertain significance ★ ⚠ same condition
HDAC4 p.Leu998Met Uncertain significance ★ same condition
HDAC4 p.Pro321Ser 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-pro1087 (accessed [today's date]).

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