Is HDAC4 p.Pro860= (c.2580C>T) pathogenic?

HDAC4 p.Pro860= (c.2580C>T) is classified Benign in HDAC4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-02). Common (popmax 65.8%, amr) — too common for a highly-penetrant pathogenic allele.

HDAC4 p.Pro860=

Q: How common is HDAC4 p.Pro860= (c.2580C>T) in the general population?

HDAC4 p.Pro860= (c.2580C>T) is common (popmax 65.8%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2580C>T · rs1063639 · VCV1174850

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 65.8%, amr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.46	GERP 3.1
Overall
CADD	6.069	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 65.8% Admixed American · 39,515/60,026 alleles

Filtering AF 65.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 65.1%

Overall 49% 790,274/1,613,816 alleles · common exomes 711,312/1,461,732 · genomes 78,962/152,084 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	65.8%	2
East Asian	65.1%	2
South Asian	60.7%	2
African / African-American	57.5%	2
Middle Eastern	53.5%	2
Remaining individualsnot grpmax-eligible	50.3%	2
Ashkenazi Jewishnot grpmax-eligible	47.9%	2
Finnishnot grpmax-eligible	46.4%	2
European (non-Finnish)	46.1%	2
Amishnot grpmax-eligible	42%	2

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.Pro860=
Coding: c.2580C>T
MANE Select: NM_001378414
dbSNP: rs1063639
Type: single nucleotide variant
Location: chr2:239082174 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.67 · 19 PDB
Residue 860: the 'histone deacetylase' region; a β-strand

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

Similar variants

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
HDAC4 p.Arg13Gln 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-pro860 (accessed [today's date]).

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