Hypophosphatemic nephrolithiasis/osteoporosis 2

Summary

Hypophosphatemic nephrolithiasis/osteoporosis 2 (MONDO:0012851) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 17

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypophosphatemic nephrolithiasis/osteoporosis 2
Mondo ID	MONDO:0012851
MeSH	C567362
OMIM	612287
DOID	DOID:0080078
UMLS	C2676782
MedGen	394127
GARD	0018347
Is cancer (heuristic)	no

Also known as: hypophosphatemic nephrolithiasis/osteoporosis type 2 · nephrolithiasis/osteoporosis, hypophosphatemic, 2 · nephrolithiasis/osteoporosis, hypophosphatemic, type 2 · NPHLOP2

Data availability: 17 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 › nephrolithiasis/osteoporosis, hypophosphatemic › hypophosphatemic nephrolithiasis/osteoporosis 2

Related subtypes (1): hypophosphatemic nephrolithiasis/osteoporosis 1

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

17 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 3 conflicting classifications of pathogenicity, 2 benign/likely benign, 1 likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1092051	NM_004252.5(NHERF1):c.902A>T (p.Asp301Val)	NHERF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1653202	NM_004252.5(NHERF1):c.85C>A (p.His29Asn)	NHERF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
5271	NM_004252.5(NHERF1):c.458G>A (p.Arg153Gln)	NHERF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1001301	NM_004252.5(NHERF1):c.425A>G (p.Lys142Arg)	NHERF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1053365	NM_004252.5(NHERF1):c.581G>A (p.Arg194Gln)	NHERF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1439727	NM_004252.5(NHERF1):c.940A>G (p.Thr314Ala)	NHERF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1494635	NM_004252.5(NHERF1):c.913A>G (p.Lys305Glu)	NHERF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2693848	NM_004252.5(NHERF1):c.910C>G (p.Pro304Ala)	NHERF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2699465	NM_004252.5(NHERF1):c.809G>A (p.Arg270His)	NHERF1	Uncertain significance	criteria provided, single submitter
3028924	NM_004252.5(NHERF1):c.107G>A (p.Gly36Asp)	NHERF1	Uncertain significance	no assertion criteria provided
4526801	NM_004252.5(NHERF1):c.565G>A (p.Glu189Lys)	NHERF1	Uncertain significance	criteria provided, single submitter
561111	NM_004252.5(NHERF1):c.657C>G (p.Ile219Met)	NHERF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
959800	NM_004252.5(NHERF1):c.469A>C (p.Met157Leu)	NHERF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1564788	NM_004252.5(NHERF1):c.888+13T>C	NHERF1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1642817	NM_004252.5(NHERF1):c.252C>T (p.Asn84=)	NHERF1	Likely benign	criteria provided, multiple submitters, no conflicts
5270	NM_004252.5(NHERF1):c.328C>G (p.Leu110Val)	NHERF1	Benign	criteria provided, multiple submitters, no conflicts
5272	NM_004252.5(NHERF1):c.673G>A (p.Glu225Lys)	NHERF1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
NHERF1	Moderate	Autosomal dominant	hypophosphatemic nephrolithiasis/osteoporosis 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NHERF1	Orphanet:244305	Dominant hypophosphatemia with nephrolithiasis or osteoporosis

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
NHERF1	HGNC:11075	ENSG00000109062	O14745	Na(+)/H(+) exchange regulatory cofactor NHE-RF1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NHERF1	Na(+)/H(+) exchange regulatory cofactor NHE-RF1	Scaffold protein that connects plasma membrane proteins with members of the ezrin/moesin/radixin family and thereby helps to link them to the actin cytoskeleton and to regulate their surface expression.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NHERF1	Scaffold/PPI	no		PDZ, EBP50_C, NHERF-1/NHERF-2

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
esophagus mucosa	1
granulocyte	1
lower esophagus mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NHERF1	284	ubiquitous	marker	granulocyte, lower esophagus mucosa, esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NHERF1	2,599

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NHERF1	O14745	22

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
renal phosphate ion absorption	1	16852.0×	0.001	NHERF1
regulation of renal phosphate excretion	1	16852.0×	0.001	NHERF1
glutathione transport	1	5617.3×	0.001	NHERF1
renal sodium ion transport	1	4213.0×	0.001	NHERF1
import across plasma membrane	1	4213.0×	0.001	NHERF1
bile acid secretion	1	3370.4×	0.001	NHERF1
negative regulation of sodium ion transport	1	2808.7×	0.001	NHERF1
gamma-aminobutyric acid import	1	2808.7×	0.001	NHERF1
gland morphogenesis	1	2407.4×	0.001	NHERF1
maintenance of epithelial cell apical/basal polarity	1	2407.4×	0.001	NHERF1
regulation of protein kinase activity	1	2407.4×	0.001	NHERF1
phospholipase C-activating dopamine receptor signaling pathway	1	2106.5×	0.001	NHERF1
negative regulation of platelet-derived growth factor receptor signaling pathway	1	1872.4×	0.001	NHERF1
microvillus assembly	1	1872.4×	0.001	NHERF1
establishment of Golgi localization	1	1872.4×	0.001	NHERF1
renal absorption	1	1685.2×	0.001	NHERF1
adenylate cyclase-activating dopamine receptor signaling pathway	1	1532.0×	0.001	NHERF1
negative regulation of fibroblast migration	1	1532.0×	0.001	NHERF1
intracellular phosphate ion homeostasis	1	1532.0×	0.001	NHERF1
establishment of epithelial cell apical/basal polarity	1	1053.2×	0.002	NHERF1
plasma membrane organization	1	887.0×	0.002	NHERF1
cerebrospinal fluid circulation	1	887.0×	0.002	NHERF1
fibroblast migration	1	842.6×	0.002	NHERF1
auditory receptor cell stereocilium organization	1	842.6×	0.002	NHERF1
negative regulation of mitotic cell cycle	1	802.5×	0.002	NHERF1
regulation of cell size	1	766.0×	0.002	NHERF1
nuclear migration	1	732.7×	0.002	NHERF1
cilium organization	1	601.9×	0.002	NHERF1
positive regulation of intrinsic apoptotic signaling pathway	1	481.5×	0.003	NHERF1
morphogenesis of an epithelium	1	343.9×	0.004	NHERF1

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
NHERF1	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
NHERF1	5	Binding:5

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	0
E	Difficult family or no structure, no drug	1	NHERF1

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)
NHERF1	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.