Is HDAC4 p.Ala445Ser (c.1333G>T) pathogenic?

HDAC4 p.Ala445Ser (c.1333G>T) is classified Uncertain significance in HDAC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-16). AlphaMissense: likely benign (0.0676); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

What condition is associated with HDAC4 p.Ala445Ser (c.1333G>T)?

HDAC4 p.Ala445Ser (c.1333G>T) is associated with Inborn genetic diseases (ClinVar).

How common is HDAC4 p.Ala445Ser (c.1333G>T) in the general population?

HDAC4 p.Ala445Ser (c.1333G>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about HDAC4 p.Ala445Ser (c.1333G>T)?

AlphaMissense predicts likely benign (score 0.0676) — an in-silico prediction, not a clinical call.

HDAC4 p.Ala445Ser

c.1333G>T · rs770769407 · VCV2471089

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0676 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0676	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -5.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.32	gain · loss 0.12 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP -1	GERP -3.9
Regional constraint	o/e 0.88	unconstrained · MANE · 18 kb · p 0.032 · regional, not allelic
Overall
CADD	12.6	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A440S vs ClinVar A445S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,876 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000479% 7/1,461,610 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,876
Admixed American	0.00167%	60,034
South Asian	0.0011%	91,078
European (non-Finnish)	0.000339%	294,979

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.Ala445Ser
Coding: c.1333G>T
MANE Select: NM_001378414
dbSNP: rs770769407
Type: single nucleotide variant
Location: chr2:239126656 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HDAC4 p.Ala445Thr Uncertain significance ★★ ⚠ same residue
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
HDAC4 p.Arg579Gln 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-ala445ser (accessed [today's date]).

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