Osteopetrosis, autosomal dominant 3

Summary

Osteopetrosis, autosomal dominant 3 (MONDO:0020848) is a disease caused by PLEKHM1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: PLEKHM1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 7

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	osteopetrosis, autosomal dominant 3
Mondo ID	MONDO:0020848
OMIM	618107
UMLS	C4748197
MedGen	1648454
GARD	0025262
Is cancer (heuristic)	no

Also known as: OPTA3 · OSTEOPETROSIS, autosomal dominant 3

Data availability: 7 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant osteopetrosis › osteopetrosis, autosomal dominant 3

Related subtypes (3): autosomal dominant osteopetrosis 2, autosomal dominant osteopetrosis 1, osteopetrosis, autosomal dominant 4

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

7 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 2 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
560304	NM_014798.3(PLEKHM1):c.2140C>T (p.Arg714Cys)	PLEKHM1	Pathogenic	no assertion criteria provided
560305	NM_014798.3(PLEKHM1):c.3053_3054del (p.Thr1018fs)	PLEKHM1	Pathogenic	no assertion criteria provided
3065942	NM_014798.3(PLEKHM1):c.94C>T (p.Gln32Ter)	PLEKHM1	Likely pathogenic	criteria provided, single submitter
3122034	NM_201589.4(MAFA):c.997C>T (p.Arg333Trp)	MAFA	Uncertain significance	criteria provided, multiple submitters, no conflicts
1174843	NM_014798.3(PLEKHM1):c.1348C>A (p.Pro450Thr)	PLEKHM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3731320	NM_014798.3(PLEKHM1):c.2717C>T (p.Ala906Val)	PLEKHM1	Uncertain significance	criteria provided, single submitter
3892118	NM_014798.3(PLEKHM1):c.1802A>G (p.Lys601Arg)	PLEKHM1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 1 · 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
PLEKHM1	Strong	Autosomal recessive	autosomal recessive osteopetrosis 6	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLEKHM1	Orphanet:210110	Intermediate osteopetrosis

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PLEKHM1	HGNC:29017	ENSG00000225190	Q9Y4G2	Pleckstrin homology domain-containing family M member 1	gencc,clinvar
MAFA	HGNC:23145	ENSG00000182759	Q8NHW3	Transcription factor MafA	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLEKHM1	Pleckstrin homology domain-containing family M member 1	Acts as a multivalent adapter protein that regulates Rab7-dependent and HOPS complex-dependent fusion events in the endolysosomal system and couples autophagic and the endocytic trafficking pathways.
MAFA	Transcription factor MafA	Transcription factor that activates insulin gene expression.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.0

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
Scaffold/PPI	1	8.6×	0.225
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLEKHM1	Scaffold/PPI	no		PH_domain, PKC_DAG/PE, Run_dom
MAFA	Transcription factor	no		bZIP_Maf, bZIP, TF_DNA-bd_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
esophagus mucosa	1
lower esophagus mucosa	1
gastrocnemius	1
hindlimb stylopod muscle	1
quadriceps femoris	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLEKHM1	134	broad	yes	lower esophagus mucosa, esophagus mucosa, blood
MAFA	89	broad	marker	quadriceps femoris, hindlimb stylopod muscle, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLEKHM1	1,038
MAFA	478

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PLEKHM1	Q9Y4G2	5
MAFA	Q8NHW3	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways 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.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of beta-cell development	1	713.8×	0.003	MAFA
Regulation of gene expression in beta cells	1	519.1×	0.003	MAFA
Developmental Biology	1	14.5×	0.069	MAFA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
autophagosome-lysosome fusion	1	601.9×	0.006	PLEKHM1
positive regulation of bone resorption	1	495.6×	0.006	PLEKHM1
positive regulation of ruffle assembly	1	495.6×	0.006	PLEKHM1
late endosome to lysosome transport	1	495.6×	0.006	PLEKHM1
lysosome localization	1	263.3×	0.008	PLEKHM1
insulin secretion	1	216.1×	0.008	MAFA
response to glucose	1	127.7×	0.012	MAFA
protein transport	1	21.9×	0.062	PLEKHM1
regulation of DNA-templated transcription	1	15.8×	0.076	MAFA
positive regulation of transcription by RNA polymerase II	1	7.4×	0.143	MAFA
regulation of transcription by RNA polymerase II	1	5.8×	0.164	MAFA

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PLEKHM1	0	0
MAFA	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	0
E	Difficult family or no structure, no drug	2	PLEKHM1, MAFA

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PLEKHM1	0	—
MAFA	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.