Is HDAC4 p.Pro48= (c.144C>T) pathogenic?

HDAC4 p.Pro48= (c.144C>T) is classified Likely benign in HDAC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-26). Ultra-rare (popmax 0.0294%, afr).

How common is HDAC4 p.Pro48= (c.144C>T) in the general population?

HDAC4 p.Pro48= (c.144C>T) is ultra-rare (popmax 0.0294%, afr) (gnomAD).

HDAC4 p.Pro48=

c.144C>T · VCV4960842

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0294%, afr)

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 3.6	GERP -0.098, phastCons 1
Overall
CADD	11.31	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0294% African / African-American · 22/74,788 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0168%

Overall 0.00143% 23/1,604,292 alleles · ultra-rare exomes 15/1,452,412 · genomes 8/151,880 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0294%	3,399
Admixed American	0.00167%	59,962

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.Pro48=
Coding: c.144C>T
MANE Select: NM_001378414
Type: single nucleotide variant
Location: chr2:239190028 (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

Similar variants

HDAC4 p.Pro48Arg Conflicting classifications of pathogenicity ★ ⚠ 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-pro48 (accessed [today's date]).

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