Is HDAC4 p.Pro651Ser (c.1951C>T) pathogenic?

HDAC4 p.Pro651Ser (c.1951C>T) is classified Likely benign in HDAC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-15). AlphaMissense: likely benign (0.0705); Very rare (popmax 0.00924%, nfe); Associated with Inborn genetic diseases.

What condition is associated with HDAC4 p.Pro651Ser (c.1951C>T)?

HDAC4 p.Pro651Ser (c.1951C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HDAC4 p.Pro651Ser (c.1951C>T) in the general population?

HDAC4 p.Pro651Ser (c.1951C>T) is very rare (popmax 0.00924%, nfe) (gnomAD).

What do computational predictors say about HDAC4 p.Pro651Ser (c.1951C>T)?

AlphaMissense predicts likely benign (score 0.0705) — an in-silico prediction, not a clinical call.

HDAC4 p.Pro651Ser

c.1951C>T · rs372756343 · VCV2484896

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0705 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00924%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0705	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -5.20	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 8.3	GERP -0.53, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 15 kb · p 0.31 · regional, not allelic
Overall
CADD	20.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P646S vs ClinVar P651S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00924% European (non-Finnish) · 109/1,179,778 alleles

Filtering AF 0.00782% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00728%

Overall 0.00813% 131/1,612,296 alleles · very rare exomes 125/1,460,058 · genomes 6/152,238 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0238%	4,198
Remaining individualsnot grpmax-eligible	0.00962%	10,397
European (non-Finnish)grpmax	0.00924%	10,824
African / African-American	0.00133%	74,944

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro651Ser
Coding: c.1951C>T
MANE Select: NM_001378414
dbSNP: rs372756343
Type: single nucleotide variant
Location: chr2:239111553 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.67 · 19 PDB
Residue 646 UniProt numbering: the 'disordered' 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.Pro651= Benign/Likely benign ★★ same residue
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

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-pro651ser (accessed [today's date]).

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