Hypercalciuria, absorptive, 2

Summary

Hypercalciuria, absorptive, 2 (MONDO:0007748) is a disease caused by ADCY10 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: ADCY10 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 56

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypercalciuria, absorptive, 2
Mondo ID	MONDO:0007748
MeSH	C562790
OMIM	143870
SNOMED CT	237886009
UMLS	C0342639
MedGen	137974
GARD	0018583
Is cancer (heuristic)	no

Also known as: HCA2 · hypercalciuria, absorptive, 2 · hypercalciuria, absorptive, susceptibility to · hypercalciuria, absorptive, type 2

Data availability: 56 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › urinary system disorder › hypercalciuria, absorptive, 2

Related subtypes (19): bacteriuria, ureteral disorder, pyuria, urinary tract obstruction, urethral disorder, kidney disorder, urinary bladder disorder, hyperglycinuria, hypercalciuria, absorptive, 1, megacystis-megaureter syndrome, postorgasmic illness syndrome, congenital urachal anomaly, urinary system neoplasm, urothelial hyperplasia, urolithiasis, urinary tract infection, meningitis-retention syndrome, paraneoplastic renal syndrome, idiopathic hypercalciuria

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

56 retrieved; paginated sample, class counts are floors:

30 uncertain significance, 12 benign/likely benign, 6 likely benign, 2 benign, 2 likely pathogenic, 1 conflicting classifications of pathogenicity, 1 pathogenic, 1 pathogenic/likely pathogenic, 1 risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
1454870	NM_018417.6(ADCY10):c.952dup (p.Tyr318fs)	ADCY10	Pathogenic	criteria provided, multiple submitters, no conflicts
3774588	NM_018417.6(ADCY10):c.3544A>T (p.Arg1182Ter)	ADCY10	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179048	NM_018417.6(ADCY10):c.2215G>T (p.Glu739Ter)	ADCY10	Likely pathogenic	criteria provided, single submitter
3236142	NM_018417.6(ADCY10):c.2430del (p.Ser810_Leu811insTer)	ADCY10	Likely pathogenic	criteria provided, single submitter
5179	ADCY10, 1438+30T-C	ADCY10	risk factor	no assertion criteria provided
1426702	NM_018417.6(ADCY10):c.229T>C (p.Tyr77His)	ADCY10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1006916	NM_018417.6(ADCY10):c.2056G>A (p.Val686Ile)	ADCY10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1014250	NM_018417.6(ADCY10):c.3667T>C (p.Tyr1223His)	ADCY10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1015315	NM_018417.6(ADCY10):c.3422G>C (p.Cys1141Ser)	ADCY10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1016266	NM_018417.6(ADCY10):c.4763G>C (p.Arg1588Thr)	ADCY10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1018816	NM_018417.6(ADCY10):c.4504C>G (p.Gln1502Glu)	ADCY10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1044489	NM_018417.6(ADCY10):c.4171T>G (p.Phe1391Val)	ADCY10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1049164	NM_018417.6(ADCY10):c.307G>T (p.Ala103Ser)	ADCY10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1052779	NM_018417.6(ADCY10):c.253+4A>G	ADCY10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1057787	NM_018417.6(ADCY10):c.4816G>A (p.Val1606Met)	ADCY10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1345495	NM_018417.6(ADCY10):c.758G>A (p.Cys253Tyr)	ADCY10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1347665	NM_018417.6(ADCY10):c.349A>G (p.Thr117Ala)	ADCY10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1403077	NM_018417.6(ADCY10):c.1025G>T (p.Cys342Phe)	ADCY10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1412468	NM_018417.6(ADCY10):c.3307A>C (p.Met1103Leu)	ADCY10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1447125	NM_018417.6(ADCY10):c.2278A>C (p.Lys760Gln)	ADCY10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1496456	NM_018417.6(ADCY10):c.3746T>C (p.Phe1249Ser)	ADCY10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1500675	NM_018417.6(ADCY10):c.878C>G (p.Thr293Arg)	ADCY10	Uncertain significance	criteria provided, multiple submitters, no conflicts
2585314	NM_018417.6(ADCY10):c.257T>C (p.Val86Ala)	ADCY10	Uncertain significance	criteria provided, multiple submitters, no conflicts
2585454	NM_018417.6(ADCY10):c.2414T>A (p.Leu805Gln)	ADCY10	Uncertain significance	criteria provided, single submitter
2627674	NM_018417.6(ADCY10):c.386T>C (p.Leu129Ser)	ADCY10	Uncertain significance	criteria provided, single submitter
3236363	NM_018417.6(ADCY10):c.4136A>G (p.Tyr1379Cys)	ADCY10	Uncertain significance	criteria provided, multiple submitters, no conflicts
3494410	NM_018417.6(ADCY10):c.3243T>A (p.Asn1081Lys)	ADCY10	Uncertain significance	criteria provided, multiple submitters, no conflicts
3599789	NM_018417.6(ADCY10):c.3760G>T (p.Ala1254Ser)	ADCY10	Uncertain significance	criteria provided, single submitter
3731501	NM_018417.6(ADCY10):c.2576A>G (p.Lys859Arg)	ADCY10	Uncertain significance	criteria provided, single submitter
387892	NM_018417.6(ADCY10):c.2872G>T (p.Glu958Ter)	ADCY10	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
ADCY10	Strong	Autosomal dominant	hypercalciuria, absorptive, 2	4
TRPV5	Limited	Autosomal recessive	hypercalciuria, absorptive, 2	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADCY10	Orphanet:2197	Idiopathic hypercalciuria

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
ADCY10	HGNC:21285	ENSG00000143199	Q96PN6	Adenylate cyclase type 10	gencc,clinvar
TRPV5	HGNC:3145	ENSG00000127412	Q9NQA5	Transient receptor potential cation channel subfamily V member 5	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADCY10	Adenylate cyclase type 10	Catalyzes the formation of the signaling molecule cAMP.
TRPV5	Transient receptor potential cation channel subfamily V member 5	Constitutively active calcium selective cation channel thought to be involved in Ca(2+) reabsorption in kidney and intestine.

Protein-family classification

Druggable: 2 · 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
Ion channel	1	55.8×	0.036
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADCY10	Enzyme (other)	yes	4.6.1.1	A/G_cyclase, Adenylate_cyclase_typ10, P-loop_NTPase
TRPV5	Ion channel	yes		Ankyrin_rpt, Ion_trans_dom, TRPV5/TRPV6

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
left testis	1
male germ cell	1
sperm	1
C1 segment of cervical spinal cord	1
adult mammalian kidney	1
kidney	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADCY10	154	tissue_specific	marker	sperm, male germ cell, left testis
TRPV5	41	tissue_specific	yes	C1 segment of cervical spinal cord, adult mammalian kidney, kidney

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ADCY10	2,182
TRPV5	1,081

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ADCY10	Q96PN6	37
TRPV5	Q9NQA5	1

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
TRP channels	1	203.9×	0.015	TRPV5
Signaling by Hedgehog	1	92.1×	0.015	ADCY10
Hedgehog ‘off’ state	1	89.2×	0.015	ADCY10
Signal Transduction	1	5.1×	0.187	ADCY10

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
negative regulation of cardiac muscle cell contraction	1	8426.0×	0.003	ADCY10
neuron projection retraction	1	4213.0×	0.003	ADCY10
positive regulation of glycogen catabolic process	1	2106.5×	0.003	ADCY10
positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway	1	2106.5×	0.003	ADCY10
regulation of urine volume	1	1685.2×	0.003	TRPV5
glucose catabolic process	1	1203.7×	0.003	ADCY10
positive regulation of vascular associated smooth muscle cell apoptotic process	1	1053.2×	0.003	ADCY10
mitochondrial ATP transmembrane transport	1	936.2×	0.003	ADCY10
positive regulation of mitochondrial depolarization	1	842.6×	0.003	ADCY10
cAMP biosynthetic process	1	702.2×	0.003	ADCY10
negative regulation of mitochondrial membrane potential	1	702.2×	0.003	ADCY10
regulation of membrane repolarization	1	648.1×	0.003	ADCY10
positive regulation of cardiac muscle cell apoptotic process	1	601.9×	0.003	ADCY10
calcium ion transport into cytosol	1	601.9×	0.003	TRPV5
regulation of mitophagy	1	601.9×	0.003	ADCY10
positive regulation of ATP biosynthetic process	1	601.9×	0.003	ADCY10
positive regulation of reactive oxygen species biosynthetic process	1	561.7×	0.003	ADCY10
neuron projection maintenance	1	561.7×	0.003	ADCY10
negative regulation of reactive oxygen species biosynthetic process	1	495.6×	0.004	ADCY10
positive regulation of ossification	1	468.1×	0.004	ADCY10
epithelial cilium movement involved in extracellular fluid movement	1	383.0×	0.004	ADCY10
positive regulation of cardiac muscle hypertrophy	1	366.4×	0.004	ADCY10
calcium ion import across plasma membrane	1	271.8×	0.005	TRPV5
neuron projection extension	1	263.3×	0.005	ADCY10
positive regulation of axon extension	1	255.3×	0.005	ADCY10
obsolete positive regulation of protein targeting to mitochondrion	1	247.8×	0.005	ADCY10
calcium ion homeostasis	1	221.7×	0.006	TRPV5
protein homotetramerization	1	118.7×	0.010	TRPV5
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1	109.4×	0.010	ADCY10
calcium ion transmembrane transport	1	105.3×	0.010	TRPV5

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
TRPV5	1	2
ADCY10	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TETRAHYDROCANNABIVARIN	2	TRPV5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ADCY10	14	Binding:14
TRPV5	3	Binding:2, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADCY10	4.6.1.1	adenylate cyclase

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
TETRAHYDROCANNABIVARIN	2	TRPV5

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	1	TRPV5
C	Druggable family + PDB, no drug	1	ADCY10
D	Druggable family + AlphaFold only, no drug	0
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)
ADCY10	14	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.