Is HDAC4 p.Leu726Val (c.2176C>G) pathogenic?

HDAC4 p.Leu726Val (c.2176C>G) is classified Uncertain significance in HDAC4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-05). AlphaMissense: likely benign (0.2019); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with HDAC4 p.Leu726Val (c.2176C>G)?

HDAC4 p.Leu726Val (c.2176C>G) is associated with Inborn genetic diseases (ClinVar).

How common is HDAC4 p.Leu726Val (c.2176C>G) in the general population?

HDAC4 p.Leu726Val (c.2176C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about HDAC4 p.Leu726Val (c.2176C>G)?

AlphaMissense predicts likely benign (score 0.2019) — an in-silico prediction, not a clinical call.

HDAC4 p.Leu726Val

c.2176C>G · rs2471206708 · VCV2474013

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2019 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2019	likely benign
REVEL	0.292	indeterminate
SaProt	LLR -9.53	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 2.7, phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 8,738 bp · p 8.8e-11 · regional, not allelic
Overall
CADD	23.5	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 L721V vs ClinVar L726V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,990 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,966 alleles · very rare exomes 4/1,461,674 · genomes 0/152,292 · joint denominator

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.Leu726Val
Coding: c.2176C>G
MANE Select: NM_001378414
dbSNP: rs2471206708
Type: single nucleotide variant
Location: chr2:239102833 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.67 · 19 PDB
Residue 721 UniProt numbering: an α-helix; the 'histone deacetylase' region

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

Similar variants

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
HDAC4 p.Arg13Gly Uncertain significance ★★ ⚠ same condition
HDAC4 p.Arg535His Uncertain significance ★★ ⚠ same condition
HDAC4 p.Arg579Gln 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-leu726val (accessed [today's date]).

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