Autosomal recessive osteopetrosis 4

Summary

Autosomal recessive osteopetrosis 4 (MONDO:0012676) is a disease caused by CLCN7 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: CLCN7 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 69

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive osteopetrosis 4
Mondo ID	MONDO:0012676
MeSH	C566933
OMIM	611490
DOID	DOID:0110944
UMLS	C1969106
MedGen	370598
GARD	0005993
Is cancer (heuristic)	no

Also known as: autosomal recessive malignant osteopetrosis caused by mutation in CLCN7 · autosomal recessive osteopetrosis caused by mutation in CLCN7 · autosomal recessive osteopetrosis type 4 · CLCN7 autosomal recessive malignant osteopetrosis · CLCN7 autosomal recessive osteopetrosis · CLCN7-related osteopetrosis · OPTB4 · osteopetrosis autosomal recessive 4 · osteopetrosis infantile malignant 2 · osteopetrosis, autosomal recessive 4 · osteopetrosis, autosomal recessive type 4

Data availability: 69 ClinVar variants · 5 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 recessive disease › autosomal recessive osteopetrosis › autosomal recessive osteopetrosis 4

Related subtypes (9): autosomal recessive osteopetrosis 1, autosomal recessive osteopetrosis 2, autosomal recessive osteopetrosis 5, autosomal recessive osteopetrosis 3, autosomal recessive osteopetrosis 6, autosomal recessive osteopetrosis 7, leukocyte adhesion deficiency 3, autosomal recessive osteopetrosis 8, osteopetrosis, autosomal recessive 9

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

69 retrieved; paginated sample, class counts are floors:

17 uncertain significance, 14 likely pathogenic, 13 pathogenic, 11 benign, 6 conflicting classifications of pathogenicity, 6 pathogenic/likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1029299	NM_001287.6(CLCN7):c.739-18G>A	CLCN7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065115	NM_001287.6(CLCN7):c.1561G>A (p.Gly521Arg)	CLCN7	Pathogenic	no assertion criteria provided
1443367	NM_001287.6(CLCN7):c.2284C>T (p.Arg762Trp)	CLCN7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1932544	NM_001287.6(CLCN7):c.1194G>A (p.Trp398Ter)	CLCN7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2664512	NM_001287.6(CLCN7):c.892dup (p.Ser298fs)	CLCN7	Pathogenic	criteria provided, single submitter
372326	NM_001287.6(CLCN7):c.2144A>G (p.Tyr715Cys)	CLCN7	Pathogenic	criteria provided, multiple submitters, no conflicts
3901171	NM_001287.6(CLCN7):c.797C>G (p.Ser266Ter)	CLCN7	Pathogenic	criteria provided, single submitter
438670	NM_001287.6(CLCN7):c.857G>A (p.Arg286Gln)	CLCN7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4688721	NM_001287.6(CLCN7):c.1828_1829del (p.Ser610fs)	CLCN7	Pathogenic	criteria provided, single submitter
545513	NM_001287.6(CLCN7):c.641A>G (p.Asn214Ser)	CLCN7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56890	NM_001287.6(CLCN7):c.296A>G (p.Tyr99Cys)	CLCN7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
585308	NM_001287.6(CLCN7):c.2250+1G>T	CLCN7	Pathogenic	criteria provided, single submitter
6860	NM_001287.6(CLCN7):c.1663C>T (p.Gln555Ter)	CLCN7	Pathogenic	no assertion criteria provided
6861	NM_001287.6(CLCN7):c.2285G>A (p.Arg762Gln)	CLCN7	Pathogenic	no assertion criteria provided
6862	NM_001287.6(CLCN7):c.2297T>C (p.Leu766Pro)	CLCN7	Pathogenic	no assertion criteria provided
6863	NM_001287.6(CLCN7):c.2299C>T (p.Arg767Trp)	CLCN7	Pathogenic	criteria provided, multiple submitters, no conflicts
6865	NM_001287.6(CLCN7):c.781A>T (p.Ile261Phe)	CLCN7	Pathogenic	no assertion criteria provided
827681	NM_001287.6(CLCN7):c.1617+119G>A	CLCN7	Pathogenic	criteria provided, multiple submitters, no conflicts
871455	NM_001287.6(CLCN7):c.139C>T (p.Gln47Ter)	CLCN7	Pathogenic	criteria provided, multiple submitters, no conflicts
1172575	NM_001287.6(CLCN7):c.2332G>T (p.Val778Phe)	CLCN7	Likely pathogenic	criteria provided, single submitter
1172576	NM_001287.6(CLCN7):c.1638del (p.Lys546fs)	CLCN7	Likely pathogenic	criteria provided, single submitter
1334479	NM_001287.6(CLCN7):c.1077C>A (p.Asn359Lys)	CLCN7	Likely pathogenic	criteria provided, single submitter
1684672	NM_001287.6(CLCN7):c.1125C>G (p.Ile375Met)	CLCN7	Likely pathogenic	criteria provided, single submitter
1684674	NM_001287.6(CLCN7):c.1681C>T (p.Arg561Trp)	CLCN7	Likely pathogenic	criteria provided, single submitter
1802224	NM_001287.6(CLCN7):c.1448-2A>G	CLCN7	Likely pathogenic	criteria provided, single submitter
2446399	NM_001287.6(CLCN7):c.1714del (p.Glu572fs)	CLCN7	Likely pathogenic	criteria provided, single submitter
2664511	NM_001287.6(CLCN7):c.1304C>T (p.Ser435Leu)	CLCN7	Likely pathogenic	criteria provided, single submitter
3064765	NM_001287.6(CLCN7):c.1394C>A (p.Ala465Asp)	CLCN7	Likely pathogenic	criteria provided, single submitter
3065777	NM_001287.6(CLCN7):c.1669+1G>C	CLCN7	Likely pathogenic	criteria provided, single submitter
3233378	NM_001287.6(CLCN7):c.1806C>G (p.Tyr602Ter)	CLCN7	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 3 · 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
CLCN7	Definitive	Autosomal recessive	autosomal recessive osteopetrosis 4	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLCN7	Orphanet:210110	Intermediate osteopetrosis
CLCN7	Orphanet:53	Albers-Schönberg osteopetrosis
CLCN7	Orphanet:667	Autosomal recessive malignant 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
CLCN7	HGNC:2025	ENSG00000103249	P51798	H(+)/Cl(-) exchange transporter 7	gencc,clinvar
SSU72	HGNC:25016	ENSG00000160075	Q9NP77	RNA polymerase II subunit A C-terminal domain phosphatase SSU72	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CLCN7	H(+)/Cl(-) exchange transporter 7	Slowly voltage-gated channel mediating the exchange of chloride ions against protons.
SSU72	RNA polymerase II subunit A C-terminal domain phosphatase SSU72	Protein phosphatase that catalyzes the dephosphorylation of the C-terminal domain of RNA polymerase II.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CLCN7	Other/Unknown	no		CBS_dom, ClC, CIC-7
SSU72	Other/Unknown	no		RNA_pol_II_suA

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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
left adrenal gland cortex	1
metanephros cortex	1
right adrenal gland cortex	1
gastrocnemius	1
muscle of leg	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CLCN7	296	ubiquitous	marker	metanephros cortex, right adrenal gland cortex, left adrenal gland cortex
SSU72	256	ubiquitous	marker	parotid gland, gastrocnemius, muscle of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLCN7	1,991
SSU72	1,918

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLCN7	P51798	9
SSU72	Q9NP77	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RNA polymerase II transcribes snRNA genes	1	77.2×	0.029	SSU72
Stimuli-sensing channels	1	68.0×	0.029	CLCN7
RNA Polymerase II Transcription	1	11.3×	0.109	SSU72
Gene expression (Transcription)	1	8.9×	0.109	SSU72

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
response to pH	1	1404.3×	0.002	CLCN7
transepithelial chloride transport	1	936.2×	0.002	CLCN7
co-transcriptional mRNA 3’-end processing, cleavage and polyadenylation pathway	1	936.2×	0.002	SSU72
termination of RNA polymerase II transcription	1	648.1×	0.002	SSU72
chloride transmembrane transport	1	118.7×	0.008	CLCN7

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CLCN7	0	0
SSU72	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
SSU72	3	Binding:3

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	CLCN7, SSU72

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)
CLCN7	0	—
SSU72	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.