Is HDAC4 p.Pro248Ala (c.742C>G) pathogenic?

HDAC4 p.Pro248Ala (c.742C>G) is classified Pathogenic in HDAC4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-03-18). AlphaMissense: likely pathogenic (0.9717); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with central hypotonia and dysmorphic facies.

What condition is associated with HDAC4 p.Pro248Ala (c.742C>G)?

HDAC4 p.Pro248Ala (c.742C>G) is associated with neurodevelopmental disorder with central hypotonia and dysmorphic facies (ClinVar).

How common is HDAC4 p.Pro248Ala (c.742C>G) in the general population?

HDAC4 p.Pro248Ala (c.742C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HDAC4 p.Pro248Ala (c.742C>G)?

AlphaMissense predicts likely pathogenic (score 0.9717) — an in-silico prediction, not a clinical call.

HDAC4 p.Pro248Ala

c.742C>G · rs2152917882 · VCV1344563

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9717 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neurodevelopmental disorder with central hypotonia and dysmorphic facies

Computational evidence

Protein change
AlphaMissense	0.9717	likely pathogenic ✓ concordant with ClinVar
REVEL	0.446	indeterminate
SaProt	LLR -13.50	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.17	constrained · MANE · 12 kb · p 5.4e-06 · regional, not allelic
Overall
CADD	26.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HDAC4
Protein: p.Pro248Ala
Coding: c.742C>G
MANE Select: NM_001378414
dbSNP: rs2152917882
Type: single nucleotide variant
Location: chr2:239144706 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.67 · 19 PDB
Residue 248: the 'interaction with mef2a' region; a UniProt-annotated variant site (in nedchf); the 'disordered' region

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

Disease context

neurodevelopmental disorder with central hypotonia and dysmorphic facies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HDAC4 p.Pro248Leu Pathogenic ★★ same residue
HDAC4 p.Thr244Lys Pathogenic/Likely pathogenic ★★ same condition
HDAC4 p.Arg132Trp Uncertain significance ★★ ⚠ same condition
HDAC4 p.Arg535His Uncertain significance ★★ ⚠ same condition
HDAC4 p.Asp982Asn Uncertain significance ★★ ⚠ same condition
HDAC4 p.Gly793Glu Uncertain significance ★★ ⚠ same condition
HDAC4 p.His556Tyr Uncertain significance ★★ ⚠ same condition
HDAC4 p.Ile766Thr 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-pro248ala (accessed [today's date]).

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