Is HDAC4 p.Pro296Ser (c.886C>T) pathogenic?

HDAC4 p.Pro296Ser (c.886C>T) is classified Uncertain significance in HDAC4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-10-22). AlphaMissense: ambiguous (0.4878); Very rare (popmax 8.47e-05%, nfe); Associated with HDAC4-related disorder.

What condition is associated with HDAC4 p.Pro296Ser (c.886C>T)?

HDAC4 p.Pro296Ser (c.886C>T) is associated with HDAC4-related disorder (ClinVar).

How common is HDAC4 p.Pro296Ser (c.886C>T) in the general population?

HDAC4 p.Pro296Ser (c.886C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about HDAC4 p.Pro296Ser (c.886C>T)?

AlphaMissense predicts ambiguous (score 0.4878) — an in-silico prediction, not a clinical call.

HDAC4 p.Pro296Ser

c.886C>T · rs568906969 · VCV3054909

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4878 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

HDAC4-related disorder

Computational evidence

Protein change
AlphaMissense	0.4878	ambiguous
REVEL	0.288	benign-leaning
SaProt	LLR -6.51	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 18 kb · p 0.032 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,964 alleles

Overall 6.2e-05% 1/1,614,058 alleles · very rare exomes 1/1,461,708 · genomes 0/152,350 · 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.Pro296Ser
Coding: c.886C>T
MANE Select: NM_001378414
dbSNP: rs568906969
Type: single nucleotide variant
Location: chr2:239139776 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.67 · 19 PDB
Residue 296: the 'interaction with mef2a' region; the 'disordered' region

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

Disease context

HDAC4-related disorder

Similar variants

HDAC4 p.Pro296= Likely benign ★ same residue
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

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-pro296ser (accessed [today's date]).

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