Is HDAC4 p.Pro527Leu (c.1580C>T) pathogenic?

HDAC4 p.Pro527Leu (c.1580C>T) is classified Likely pathogenic in HDAC4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-08-31). AlphaMissense: ambiguous (0.4716); Very rare (popmax 0.00267%, afr); Associated with plasma cell myeloma.

What condition is associated with HDAC4 p.Pro527Leu (c.1580C>T)?

HDAC4 p.Pro527Leu (c.1580C>T) is associated with plasma cell myeloma (ClinVar).

How common is HDAC4 p.Pro527Leu (c.1580C>T) in the general population?

HDAC4 p.Pro527Leu (c.1580C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

How is Multiple myeloma inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about HDAC4 p.Pro527Leu (c.1580C>T)?

AlphaMissense predicts ambiguous (score 0.4716) — an in-silico prediction, not a clinical call.

HDAC4 p.Pro527Leu

c.1580C>T · rs372078034 · VCV800319

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4716 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

plasma cell myeloma

Computational evidence

Protein change
AlphaMissense	0.4716	ambiguous
REVEL	0.247	benign-leaning
SaProt	LLR -6.27	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 15 kb · p 0.31 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P522L vs ClinVar P527L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,930 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00093% 15/1,613,204 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,465
European (non-Finnish)	0.0011%	90,765

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.Pro527Leu
Coding: c.1580C>T
MANE Select: NM_001378414
dbSNP: rs372078034
Type: single nucleotide variant
Location: chr2:239115264 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.67 · 19 PDB
Residue 527: the 'disordered' region

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

Disease context

plasma cell myeloma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Multiple myeloma (Orphanet):

Inheritance: Not applicable
Onset: Adult
Prevalence: 1-9 / 100 000 (United States)

Similar variants

HDAC4 p.Pro527= Benign ★★ same residue
HDAC4 p.Pro527Gln Uncertain significance ★ ⚠ same residue
HDAC4 p.Pro248Leu Pathogenic ★★ same type
HDAC4 p.Thr244Lys Pathogenic/Likely pathogenic ★★ same type
HDAC4 c.865+8G>A Uncertain significance ★★ same type
HDAC4 p.Ala445Thr Uncertain significance ★★ ⚠ same type
HDAC4 p.Ala620Thr Uncertain significance ★★ ⚠ same type
HDAC4 p.Ala91Thr Uncertain significance ★★ ⚠ same type

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-pro527leu (accessed [today's date]).

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