hypophosphatemic rickets, X-linked recessive

Summary

hypophosphatemic rickets, X-linked recessive (MONDO:0010358) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 97

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypophosphatemic rickets, X-linked recessive
Mondo ID	MONDO:0010358
OMIM	300554
DOID	DOID:0080353
UMLS	C1845168
MedGen	335115
GARD	0015011
Is cancer (heuristic)	no

Also known as: CLCN5 X-linked hypophosphatemic rickets · hypophosphatemic rickets, X-linked recessive · X-linked hypophosphatemic rickets caused by mutation in CLCN5

Data availability: 97 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › X-linked recessive disease › hypophosphatemic rickets, X-linked recessive

Related subtypes (11): retinitis pigmentosa 6, Brunner syndrome, X-linked lymphoproliferative disease due to XIAP deficiency, blue cone monochromacy, recessive X-linked ichthyosis, X-linked complicated spastic paraplegia type 1, X-linked recessive ocular albinism, X-linked lymphoproliferative disease due to SH2D1A deficiency, holoprosencephaly 13, X-linked, X-linked recessive mitochondrial myopathy, IFAP syndrome 1, with or without BRESHECK syndrome

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

97 retrieved; paginated sample, class counts are floors:

39 uncertain significance, 22 likely pathogenic, 12 pathogenic, 9 conflicting classifications of pathogenicity, 6 pathogenic/likely pathogenic, 4 likely benign, 4 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
11802	NM_001127898.4(CLCN5):c.941C>T (p.Ser314Leu)	CLCN5	Pathogenic	criteria provided, multiple submitters, no conflicts
11803	NM_001127898.4(CLCN5):c.1238G>A (p.Trp413Ter)	CLCN5	Pathogenic	criteria provided, single submitter
1334562	NM_001127898.4(CLCN5):c.1014+1G>A	CLCN5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207994	NM_001127898.4(CLCN5):c.310C>T (p.Arg104Ter)	CLCN5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207996	NM_001127898.4(CLCN5):c.1249C>T (p.Arg417Ter)	CLCN5	Pathogenic	criteria provided, multiple submitters, no conflicts
207998	NM_001127898.4(CLCN5):c.1756C>T (p.Arg586Trp)	CLCN5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207999	NM_001127898.4(CLCN5):c.2119C>T (p.Arg707Ter)	CLCN5	Pathogenic	criteria provided, multiple submitters, no conflicts
208000	NM_001127898.4(CLCN5):c.2362C>T (p.Arg788Ter)	CLCN5	Pathogenic	criteria provided, multiple submitters, no conflicts
208007	Single allele	CLCN5	Pathogenic	no assertion criteria provided
2748234	NM_001127898.4(CLCN5):c.933+1G>A	CLCN5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3598361	NM_001127898.4(CLCN5):c.342del (p.Trp115fs)	CLCN5	Pathogenic	criteria provided, single submitter
3598363	NM_001127898.4(CLCN5):c.371dup (p.Ser126fs)	CLCN5	Pathogenic	criteria provided, single submitter
3598380	NM_001127898.4(CLCN5):c.1275T>G (p.Tyr425Ter)	CLCN5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4526845	NM_001127898.4(CLCN5):c.1726G>A (p.Gly576Arg)	CLCN5	Pathogenic	criteria provided, single submitter
4526846	NM_001127898.4(CLCN5):c.1799G>T (p.Gly600Val)	CLCN5	Pathogenic	criteria provided, single submitter
4526848	NM_001127898.4(CLCN5):c.603+1G>T	CLCN5	Pathogenic	criteria provided, single submitter
488682	NM_001127898.4(CLCN5):c.292C>T (p.Arg98Ter)	CLCN5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
932948	NM_001127898.4(CLCN5):c.1176del (p.Phe392fs)	CLCN5	Pathogenic	criteria provided, single submitter
4075824	Single allele	CENPVL2	Likely pathogenic	criteria provided, single submitter
3236753	NM_001127898.4(CLCN5):c.1633C>T (p.Gln545Ter)	CLCN5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3598359	NM_001127898.4(CLCN5):c.277_282delinsTCTC (p.Val93fs)	CLCN5	Likely pathogenic	criteria provided, single submitter
3598362	NM_001127898.4(CLCN5):c.348del (p.Ala116_Leu117insTer)	CLCN5	Likely pathogenic	criteria provided, single submitter
3598364	NM_001127898.4(CLCN5):c.416-1G>A	CLCN5	Likely pathogenic	criteria provided, single submitter
3598367	NM_001127898.4(CLCN5):c.567G>A (p.Trp189Ter)	CLCN5	Likely pathogenic	criteria provided, single submitter
3598372	NM_001127898.4(CLCN5):c.772A>T (p.Lys258Ter)	CLCN5	Likely pathogenic	criteria provided, single submitter
3598377	NM_001127898.4(CLCN5):c.1052C>A (p.Ser351Ter)	CLCN5	Likely pathogenic	criteria provided, single submitter
3598378	NM_001127898.4(CLCN5):c.1137dup (p.Phe380fs)	CLCN5	Likely pathogenic	criteria provided, single submitter
3598387	NM_001127898.4(CLCN5):c.1485C>G (p.Tyr495Ter)	CLCN5	Likely pathogenic	criteria provided, single submitter
3598389	NM_001127898.4(CLCN5):c.1595G>A (p.Gly532Asp)	CLCN5	Likely pathogenic	criteria provided, single submitter
3598390	NM_001127898.4(CLCN5):c.1601_1602dup (p.Ala535Ter)	CLCN5	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLCN5	Orphanet:93622	Dent disease type 1

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
CLCN5	HGNC:2023	ENSG00000171365	P51795	H(+)/Cl(-) exchange transporter 5	clinvar
CENPVL2	HGNC:43879	ENSG00000283093	P0DPI3	Centromere protein V-like protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CLCN5	H(+)/Cl(-) exchange transporter 5	Proton-coupled chloride transporter.

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)
CLCN5	Other/Unknown	no		CBS_dom, ClC, Cl_channel-5
CENPVL2	Other/Unknown	no		CENP-V/GFA, Mss4-like_sf, CENP-V-like

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
corpus epididymis	1
renal medulla	1
secondary oocyte	1
cortical plate	1
hypothalamus	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CLCN5	218	ubiquitous	marker	renal medulla, secondary oocyte, corpus epididymis
CENPVL2	31		yes	cortical plate, ventricular zone, hypothalamus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLCN5	1,345
CENPVL2	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLCN5	P51795	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CENPVL2	P0DPI3	71.90

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Stimuli-sensing channels	1	135.9×	0.007	CLCN5

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
renal system process	1	1123.5×	0.004	CLCN5
chloride transport	1	455.5×	0.004	CLCN5
monoatomic ion transmembrane transport	1	208.1×	0.006	CLCN5
endocytosis	1	95.2×	0.011	CLCN5

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
CLCN5	0	0
CENPVL2	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	CLCN5, CENPVL2

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)
CLCN5	0	—
CENPVL2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.