Is HDAC4 p.Ser290Pro (c.868T>C) pathogenic?

HDAC4 p.Ser290Pro (c.868T>C) is classified Uncertain significance in HDAC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-27). AlphaMissense: likely benign (0.162); Very rare (popmax 0.000593%, nfe); Associated with HDAC4-related disorder.

What condition is associated with HDAC4 p.Ser290Pro (c.868T>C)?

HDAC4 p.Ser290Pro (c.868T>C) is associated with HDAC4-related disorder (ClinVar).

How common is HDAC4 p.Ser290Pro (c.868T>C) in the general population?

HDAC4 p.Ser290Pro (c.868T>C) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about HDAC4 p.Ser290Pro (c.868T>C)?

AlphaMissense predicts likely benign (score 0.162) — an in-silico prediction, not a clinical call.

HDAC4 p.Ser290Pro

c.868T>C · rs2152900682 · VCV2633500

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.162 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

HDAC4-related disorder

Computational evidence

Protein change
AlphaMissense	0.162	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -8.52	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.2	GERP 1.2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 18 kb · p 0.032 · regional, not allelic
Overall
CADD	23.6	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,179,710 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,612,874 alleles · very rare exomes 7/1,461,364 · genomes 0/151,510 · 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.Ser290Pro
Coding: c.868T>C
MANE Select: NM_001378414
dbSNP: rs2152900682
Type: single nucleotide variant
Location: chr2:239139794 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.67 · 19 PDB
Residue 290: 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.Ser290= Benign/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-ser290pro (accessed [today's date]).

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