Is HDAC4 p.Pro16Ala (c.46C>G) pathogenic?

HDAC4 p.Pro16Ala (c.46C>G) is classified Uncertain significance in HDAC4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-01). AlphaMissense: likely benign (0.0708); Absent from gnomAD v4.1; Associated with HDAC4-related disorder.

What condition is associated with HDAC4 p.Pro16Ala (c.46C>G)?

HDAC4 p.Pro16Ala (c.46C>G) is associated with HDAC4-related disorder (ClinVar).

How common is HDAC4 p.Pro16Ala (c.46C>G) in the general population?

HDAC4 p.Pro16Ala (c.46C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HDAC4 p.Pro16Ala (c.46C>G)?

AlphaMissense predicts likely benign (score 0.0708) — an in-silico prediction, not a clinical call.

HDAC4 p.Pro16Ala

c.46C>G · rs2474801435 · VCV2631581

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0708 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

HDAC4-related disorder

Computational evidence

Protein change
AlphaMissense	0.0708	likely benign
REVEL	0.141	moderately benign-leaning
SaProt	LLR -6.14	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 9.5	GERP 2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 196 kb · p 0.00035 · regional, not allelic
Overall
CADD	23.2	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

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.Pro16Ala
Coding: c.46C>G
MANE Select: NM_001378414
dbSNP: rs2474801435
Type: single nucleotide variant
Location: chr2:239236641 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.67 · 19 PDB

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

Disease context

HDAC4-related disorder

Similar variants

HDAC4 p.Thr244Lys Pathogenic/Likely pathogenic ★★ same condition
HDAC4 p.Met49Val 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
HDAC4 p.Pro321Ser Uncertain significance ★ ⚠ same condition
HDAC4 p.Ser290Pro 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-pro16ala (accessed [today's date]).

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