Cardiomyopathy, familial hypertrophic 27

Summary

Cardiomyopathy, familial hypertrophic 27 (MONDO:0054838) is a disease caused by ALPK3 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ALPK3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 171

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cardiomyopathy, familial hypertrophic 27
Mondo ID	MONDO:0054838
OMIM	618052
DOID	DOID:0061102
UMLS	C4748014
MedGen	1648325
GARD	0025983
Is cancer (heuristic)	no

Also known as: CMH27

Data availability: 171 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › intrinsic cardiomyopathy › hypertrophic cardiomyopathy › familial hypertrophic cardiomyopathy › cardiomyopathy, familial hypertrophic 27

Related subtypes (39): hypertrophic cardiomyopathy 2, hypertrophic cardiomyopathy 3, hypertrophic cardiomyopathy 4, Beckwith-Wiedemann syndrome, myotonic dystrophy type 1, hypertrophic cardiomyopathy 1, very long chain acyl-CoA dehydrogenase deficiency, multiple acyl-CoA dehydrogenase deficiency, 46,XY complete gonadal dysgenesis, hypertrophic cardiomyopathy 6, dilated cardiomyopathy 1C, hypertrophic cardiomyopathy 25, hypertrophic cardiomyopathy 8, hypertrophic cardiomyopathy 10, long chain 3-hydroxyacyl-CoA dehydrogenase deficiency, cardiomyopathy-hypotonia-lactic acidosis syndrome, hypertrophic cardiomyopathy 11, hypertrophic cardiomyopathy 12, hypertrophic cardiomyopathy 13, hypertrophic cardiomyopathy 14, hypertrophic cardiomyopathy 15, hypertrophic cardiomyopathy 7, hypertrophic cardiomyopathy 9, hypertrophic cardiomyopathy 16, hypertrophic cardiomyopathy 17, hypertrophic cardiomyopathy 18, hypertrophic cardiomyopathy 19, hypertrophic cardiomyopathy 20, hypertrophic cardiomyopathy 21, dilated cardiomyopathy 1KK, hypertrophic cardiomyopathy 26, Noonan syndrome and Noonan-related syndrome, long chain acyl-CoA dehydrogenase deficiency, cardiomyopathy, familial hypertrophic, 28, cardiomyopathy, familial hypertrophic, 23, with or without ventricular noncompaction, cardiomyopathy, familial restrictive, 5, cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, cardiomyopathy, familial hypertrophic, 30, atrial, cardiomyopathy, familial hypertrophic, 31

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

171 retrieved; paginated sample, class counts are floors:

45 uncertain significance, 28 likely pathogenic, 24 pathogenic, 22 conflicting classifications of pathogenicity, 19 benign/likely benign, 16 pathogenic/likely pathogenic, 10 likely benign, 7 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1028191	NM_020778.5(ALPK3):c.913C>T (p.Gln305Ter)	ALPK3	Pathogenic	criteria provided, single submitter
1064814	NM_020778.5(ALPK3):c.4154del (p.Pro1385fs)	ALPK3	Pathogenic	criteria provided, multiple submitters, no conflicts
1186088	NM_020778.5(ALPK3):c.4213C>T (p.Arg1405Ter)	ALPK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1187004	NM_020778.5(ALPK3):c.589G>T (p.Glu197Ter)	ALPK3	Pathogenic	criteria provided, multiple submitters, no conflicts
1323072	NM_020778.5(ALPK3):c.2471delinsTCATT (p.Ser824fs)	ALPK3	Pathogenic	criteria provided, single submitter
1342709	NM_020778.5(ALPK3):c.297del (p.Ile99fs)	ALPK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1414127	NM_020778.5(ALPK3):c.3340C>T (p.Arg1114Ter)	ALPK3	Pathogenic	criteria provided, multiple submitters, no conflicts
1421174	NM_020778.5(ALPK3):c.3292G>T (p.Glu1098Ter)	ALPK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1447592	NM_020778.5(ALPK3):c.3535del (p.Glu1179fs)	ALPK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459844	NM_020778.5(ALPK3):c.3936_3937del (p.Asp1312fs)	ALPK3	Pathogenic	criteria provided, multiple submitters, no conflicts
1699145	NM_020778.5(ALPK3):c.3381del (p.Ser1129fs)	ALPK3	Pathogenic	criteria provided, single submitter
1740499	NM_020778.5(ALPK3):c.3818-1G>C	ALPK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1754800	NM_020778.5(ALPK3):c.61_62delinsT (p.Gly21fs)	ALPK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1799378	NM_020778.5(ALPK3):c.2455C>T (p.Arg819Ter)	ALPK3	Pathogenic	criteria provided, multiple submitters, no conflicts
1929460	NM_020778.5(ALPK3):c.2668C>T (p.Gln890Ter)	ALPK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1953459	NM_020778.5(ALPK3):c.4290C>G (p.Tyr1430Ter)	ALPK3	Pathogenic	criteria provided, multiple submitters, no conflicts
1996534	NM_020778.5(ALPK3):c.607G>T (p.Glu203Ter)	ALPK3	Pathogenic	criteria provided, multiple submitters, no conflicts
2563940	NM_020778.5(ALPK3):c.3772C>T (p.Gln1258Ter)	ALPK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2572382	NM_020778.5(ALPK3):c.3409_3436del (p.Pro1137fs)	ALPK3	Pathogenic	criteria provided, single submitter
2572503	NM_020778.5(ALPK3):c.691C>T (p.Gln231Ter)	ALPK3	Pathogenic	criteria provided, multiple submitters, no conflicts
2978316	NM_020778.5(ALPK3):c.208C>T (p.Gln70Ter)	ALPK3	Pathogenic	criteria provided, multiple submitters, no conflicts
3376704	NM_020778.5(ALPK3):c.2260G>T (p.Glu754Ter)	ALPK3	Pathogenic	criteria provided, single submitter
3689438	NM_020778.5(ALPK3):c.2631_2634del (p.Ser878fs)	ALPK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3747846	ALPK3, 2-BP DEL, 1531AA	ALPK3	Pathogenic	no assertion criteria provided
3764698	NM_020778.5(ALPK3):c.109del (p.Arg37fs)	ALPK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3775568	NM_020778.5(ALPK3):c.2841_2848del (p.Gly948fs)	ALPK3	Pathogenic	criteria provided, single submitter
424341	NM_020778.5(ALPK3):c.1093C>T (p.Gln365Ter)	ALPK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4292172	NM_020778.5(ALPK3):c.663_664delinsG (p.Phe221fs)	ALPK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4685857	NM_020778.5(ALPK3):c.1445_1446del (p.Arg482fs)	ALPK3	Pathogenic	criteria provided, single submitter
4796557	NM_020778.5(ALPK3):c.1337_1340del (p.Pro446fs)	ALPK3	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 0 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ALPK3	Definitive	Autosomal recessive	cardiomyopathy, familial hypertrophic 27	7

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ALPK3	HGNC:17574	ENSG00000136383	Q96L96	Alpha-protein kinase 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALPK3	Alpha-protein kinase 3	Involved in cardiomyocyte differentiation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALPK3	Kinase	yes		Ig_sub2, Ig_sub, a-kinase_dom

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
gluteal muscle	1
hindlimb stylopod muscle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALPK3	201	broad	yes	gastrocnemius, hindlimb stylopod muscle, gluteal muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALPK3	878

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ALPK3	Q96L96	49.15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cardiac muscle cell development	1	624.1×	0.003	ALPK3
heart development	1	78.8×	0.013	ALPK3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALPK3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ALPK3	10	Binding:10

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ALPK3
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ALPK3	10	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.