Familial hypocalciuric hypercalcemia 3

Summary

Familial hypocalciuric hypercalcemia 3 (MONDO:0010926) is a disease caused by AP2S1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: AP2S1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 17

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial hypocalciuric hypercalcemia 3
Mondo ID	MONDO:0010926
MeSH	C537147
OMIM	600740
Orphanet	101050
DOID	DOID:0060702
UMLS	C1833372
MedGen	322173
GARD	0002878
Is cancer (heuristic)	no

Also known as: AP2S1 familial hypocalciuric hypercalcemia · familial benign hypercalcemia, Oklahoma variant · familial hypocalciuric hypercalcemia caused by mutation in AP2S1 · familial hypocalciuric hypercalcemia type 3 · FBH3 · FBHOk · FHH type 3 · HHC3 · hpocalciuric hypercalcemia, type III · hypocalciuric hypercalcemia, familial, type 3 · hypocalciuric hypercalcemia, familial, type III

Data availability: 17 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › mineral metabolism disease › calcium metabolic disease › hypercalcemia disease › familial hypocalciuric hypercalcemia › familial hypocalciuric hypercalcemia 3

Related subtypes (2): familial hypocalciuric hypercalcemia 1, familial hypocalciuric hypercalcemia 2

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:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
39424	NM_004069.6(AP2S1):c.43C>T (p.Arg15Cys)	AP2S1	Pathogenic	criteria provided, multiple submitters, no conflicts
39425	NM_004069.6(AP2S1):c.44G>T (p.Arg15Leu)	AP2S1	Pathogenic	criteria provided, multiple submitters, no conflicts
39426	NM_004069.6(AP2S1):c.44G>A (p.Arg15His)	AP2S1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2848182	NM_004069.6(AP2S1):c.285C>T (p.Phe95=)	AP2S1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
421594	NM_004069.6(AP2S1):c.28C>T (p.Arg10Trp)	AP2S1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
999396	NM_004069.6(AP2S1):c.267+7C>T	AP2S1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1395311	NM_004069.6(AP2S1):c.153+5C>T	AP2S1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2150903	NM_004069.6(AP2S1):c.335C>T (p.Thr112Met)	AP2S1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2893299	NM_004069.6(AP2S1):c.386C>T (p.Thr129Met)	AP2S1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3584050	NM_004069.6(AP2S1):c.418T>A (p.Ser140Thr)	AP2S1	Uncertain significance	criteria provided, single submitter
3584052	NM_004069.6(AP2S1):c.13A>G (p.Ile5Val)	AP2S1	Uncertain significance	criteria provided, single submitter
1167857	NM_004069.6(AP2S1):c.261C>T (p.Phe87=)	AP2S1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1192407	NM_004069.6(AP2S1):c.154-32T>G	AP2S1	Benign	criteria provided, multiple submitters, no conflicts
1596996	NM_004069.6(AP2S1):c.75T>C (p.Asp25=)	AP2S1	Likely benign	criteria provided, multiple submitters, no conflicts
1600451	NM_004069.6(AP2S1):c.4-14_4-12del	AP2S1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1654562	NM_004069.6(AP2S1):c.111C>T (p.Ala37=)	AP2S1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1670990	NM_004069.6(AP2S1):c.387G>A (p.Thr129=)	AP2S1	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
AP2S1	Strong	Autosomal dominant	familial hypocalciuric hypercalcemia 3	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AP2S1	Orphanet:101050	Familial hypocalciuric hypercalcemia type 3

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
AP2S1	HGNC:565	ENSG00000042753	P53680	AP-2 complex subunit sigma	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AP2S1	AP-2 complex subunit sigma	Component of the adaptor protein complex 2 (AP-2).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AP2S1	Other/Unknown	no		Clathrin_sm-chain_CS, Longin-like_dom_sf, AP_complex_ssu

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
lower esophagus mucosa	1
right adrenal gland	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AP2S1	299	ubiquitous	marker	lower esophagus mucosa, stromal cell of endometrium, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AP2S1	2,185

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AP2S1	P53680	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 42. Enrichment computed across 1 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
Nef Mediated CD8 Down-regulation	1	1631.4×	0.007	AP2S1
Nef Mediated CD4 Down-regulation	1	1268.9×	0.007	AP2S1
WNT5A-dependent internalization of FZD2, FZD5 and ROR2	1	878.5×	0.007	AP2S1
Retrograde neurotrophin signalling	1	815.7×	0.007	AP2S1
WNT5A-dependent internalization of FZD4	1	761.3×	0.007	AP2S1
VLDLR internalisation and degradation	1	713.8×	0.007	AP2S1
Trafficking of GluR2-containing AMPA receptors	1	671.8×	0.007	AP2S1
Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters	1	634.4×	0.007	AP2S1
The role of Nef in HIV-1 replication and disease pathogenesis	1	634.4×	0.007	AP2S1
LDL clearance	1	543.8×	0.008	AP2S1
Plasma lipoprotein clearance	1	475.8×	0.008	AP2S1
Host Interactions of HIV factors	1	335.9×	0.010	AP2S1
PCP/CE pathway	1	300.5×	0.010	AP2S1
Beta-catenin independent WNT signaling	1	292.8×	0.010	AP2S1
Dengue Virus Attachment and Entry	1	259.6×	0.011	AP2S1
Plasma lipoprotein assembly, remodeling, and clearance	1	228.4×	0.011	AP2S1
Recycling pathway of L1	1	223.9×	0.011	AP2S1
EPH-ephrin mediated repulsion of cells	1	219.6×	0.011	AP2S1
Signaling by NTRK1 (TRKA)	1	196.9×	0.011	AP2S1
Signaling by NTRKs	1	181.3×	0.012	AP2S1
EPH-Ephrin signaling	1	165.5×	0.012	AP2S1
L1CAM interactions	1	120.2×	0.015	AP2S1
HIV Infection	1	119.0×	0.015	AP2S1
Potential therapeutics for SARS	1	114.2×	0.015	AP2S1
Signaling by WNT	1	112.0×	0.015	AP2S1
Cargo recognition for clathrin-mediated endocytosis	1	104.8×	0.015	AP2S1
MHC class II antigen presentation	1	89.2×	0.017	AP2S1
Clathrin-mediated endocytosis	1	85.2×	0.018	AP2S1
SARS-CoV Infections	1	55.4×	0.026	AP2S1
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.027	AP2S1

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
postsynaptic neurotransmitter receptor internalization	1	2106.5×	0.003	AP2S1
clathrin coat assembly	1	887.0×	0.003	AP2S1
clathrin-dependent endocytosis	1	581.1×	0.003	AP2S1
regulation of endocytosis	1	481.5×	0.003	AP2S1
synaptic vesicle endocytosis	1	432.1×	0.003	AP2S1
vesicle-mediated transport	1	96.3×	0.012	AP2S1
intracellular protein transport	1	64.8×	0.015	AP2S1

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
AP2S1	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
AP2S1	1	Binding:1

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	AP2S1

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)
AP2S1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.