ALPK3

Chr 15AR

alpha kinase 3

Also known as: CMH27, MAK, MIDORI

NCBI Gene: 57538 ENSG00000136383 UniProt: Q96L96 OMIM: 617608

The protein is a serine/threonine kinase that functions in cardiomyocyte differentiation and cardiac muscle cell development. Biallelic mutations cause autosomal recessive familial hypertrophic cardiomyopathy. The gene shows tolerance to loss-of-function variants in the general population (low constraint), and additional clinical information is available in GeneReviews.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

Predicted to enable ATP binding activity; protein serine kinase activity; and protein serine/threonine kinase activity. Predicted to be involved in cardiac muscle cell development. Predicted to be active in nucleus. Implicated in hypertrophic cardiomyopathy 27. [provided by Alliance of Genome Resources, Jul 2025]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Cardiomyopathy, familial hypertrophic 27MIM #618052

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · hypertrophic cardiomyopathy · AR · ClinGen 2022

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.91

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — ALPK3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.91LOEUF

pLI 0.000

Z-score 2.15

OE 0.72 (0.57–0.91)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.13Z-score

OE missense 0.99 (0.94–1.04)

1061 obs / 1073.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.72 (0.57–0.91)

0≤0.351.4

Missense OE?0.99 (0.94–1.04)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 48 / 67.0Missense obs/exp: 1061 / 1073.1Syn Z: -0.39

Background carrier burden — how many people carry a rare variant somewhere in ALPK3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 19

2,424 rare PASS variants

Rare truncating (LoF)

1 in 450

281 rare PASS variants

Rare synonymous (reference)

1 in 43

1,003 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ALPK3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 25	1 in 390
South Asian	~43k	1 in 23	1 in 430
Remaining (unassigned)	~30k	1 in 21	1 in 310
European (Finnish)	~27k	1 in 70	1 in 3,800
Admixed American	~22k	1 in 22	1 in 650
African / African American	~21k	1 in 17	1 in 960
East Asian	~20k	1 in 21	1 in 870
Ashkenazi Jewish	~13k	1 in 70	none seen
Middle Eastern	~2,884	1 in 31	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 13 of 14 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 14.? see exons ↓