Familial hypocalciuric hypercalcemia 2

Summary

Familial hypocalciuric hypercalcemia 2 (MONDO:0007792) is a disease caused by GNA11 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: GNA11 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 54

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial hypocalciuric hypercalcemia 2
Mondo ID	MONDO:0007792
MeSH	C537146
OMIM	145981
Orphanet	101049
DOID	DOID:0060701
UMLS	C1840347
MedGen	374447
GARD	0009758
Is cancer (heuristic)	no

Also known as: familial hypocalciuric hypercalcemia type 2 · FBH2 · FHH type 2 · HHC2 · hpocalciuric hypercalcemia, type II · hypercalcemia, familial benign type 2 · hypocalciuric hypercalcemia, familial, type 2 · hypocalciuric hypercalcemia, familial, type II

Data availability: 54 ClinVar variants · 5 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 2

Related subtypes (2): familial hypocalciuric hypercalcemia 1, familial hypocalciuric hypercalcemia 3

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

54 retrieved; paginated sample, class counts are floors:

27 uncertain significance, 12 likely benign, 6 benign/likely benign, 4 conflicting classifications of pathogenicity, 2 likely pathogenic, 2 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
60661	NM_002067.5(GNA11):c.595ATC[1] (p.Ile200del)	GNA11	Pathogenic	no assertion criteria provided
60662	NM_002067.5(GNA11):c.404T>A (p.Leu135Gln)	GNA11	Pathogenic	no assertion criteria provided
60665	NM_002067.5(GNA11):c.178C>T (p.Arg60Cys)	GNA11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1285379	NM_002067.5(GNA11):c.161C>T (p.Thr54Met)	GNA11	Likely pathogenic	criteria provided, single submitter
3583562	NM_002067.5(GNA11):c.446G>A (p.Arg149His)	GNA11	Likely pathogenic	criteria provided, single submitter
1041640	NM_002067.5(GNA11):c.138C>T (p.Gly46=)	GNA11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1346018	NM_002067.5(GNA11):c.605+10G>A	GNA11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1594049	NM_002067.5(GNA11):c.549C>T (p.Arg183=)	GNA11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2422960	NM_002067.5(GNA11):c.889+15G>A	GNA11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1021156	NM_002067.5(GNA11):c.805G>A (p.Val269Ile)	GNA11	Uncertain significance	criteria provided, multiple submitters, no conflicts
1046037	NM_002067.5(GNA11):c.889+4C>T	GNA11	Uncertain significance	criteria provided, multiple submitters, no conflicts
1380445	NM_002067.5(GNA11):c.605+5C>T	GNA11	Uncertain significance	criteria provided, multiple submitters, no conflicts
1441235	NM_002067.5(GNA11):c.889+5G>A	GNA11	Uncertain significance	criteria provided, multiple submitters, no conflicts
1494776	NM_002067.5(GNA11):c.592A>C (p.Asn198His)	GNA11	Uncertain significance	criteria provided, multiple submitters, no conflicts
1926750	NM_002067.5(GNA11):c.606-2A>G	GNA11	Uncertain significance	criteria provided, multiple submitters, no conflicts
1955349	NM_002067.5(GNA11):c.916C>T (p.Arg306Trp)	GNA11	Uncertain significance	criteria provided, multiple submitters, no conflicts
2026827	NM_002067.5(GNA11):c.447C>T (p.Arg149=)	GNA11	Uncertain significance	criteria provided, multiple submitters, no conflicts
2755656	NM_002067.5(GNA11):c.899G>A (p.Arg300Gln)	GNA11	Uncertain significance	criteria provided, multiple submitters, no conflicts
2891272	NM_002067.5(GNA11):c.880G>A (p.Glu294Lys)	GNA11	Uncertain significance	criteria provided, multiple submitters, no conflicts
3583558	NM_002067.5(GNA11):c.29G>A (p.Cys10Tyr)	GNA11	Uncertain significance	criteria provided, single submitter
3583559	NM_002067.5(GNA11):c.205del (p.Glu69fs)	GNA11	Uncertain significance	criteria provided, single submitter
3583560	NM_002067.5(GNA11):c.239A>T (p.Tyr80Phe)	GNA11	Uncertain significance	criteria provided, single submitter
3583561	NM_002067.5(GNA11):c.314A>G (p.Gln105Arg)	GNA11	Uncertain significance	criteria provided, single submitter
3583563	NM_002067.5(GNA11):c.469G>A (p.Ala157Thr)	GNA11	Uncertain significance	criteria provided, single submitter
3583564	NM_002067.5(GNA11):c.477-14C>T	GNA11	Uncertain significance	criteria provided, single submitter
3583565	NM_002067.5(GNA11):c.477-12G>T	GNA11	Uncertain significance	criteria provided, single submitter
3583566	NM_002067.5(GNA11):c.485C>G (p.Thr162Ser)	GNA11	Uncertain significance	criteria provided, single submitter
3583567	NM_002067.5(GNA11):c.595A>G (p.Ile199Val)	GNA11	Uncertain significance	criteria provided, single submitter
3583568	NM_002067.5(GNA11):c.606-16C>A	GNA11	Uncertain significance	criteria provided, single submitter
3583569	NM_002067.5(GNA11):c.778A>G (p.Thr260Ala)	GNA11	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 8 · 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
GNA11	Strong	Autosomal dominant	familial hypocalciuric hypercalcemia 2	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GNA11	Orphanet:101049	Familial hypocalciuric hypercalcemia type 2
GNA11	Orphanet:1556	Cutis marmorata telangiectatica congenita
GNA11	Orphanet:39044	Uveal melanoma
GNA11	Orphanet:428	Autosomal dominant hypocalcemia
GNA11	Orphanet:675359	Anastomosing haemangioma
GNA11	Orphanet:714737	Diffuse capillary malformation with overgrowth
GNA11	Orphanet:79483	Phakomatosis cesioflammea
GNA11	Orphanet:79484	Phakomatosis cesiomarmorata

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
GNA11	HGNC:4379	ENSG00000088256	P29992	Guanine nucleotide-binding protein subunit alpha-11	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GNA11	Guanine nucleotide-binding protein subunit alpha-11	Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades.

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)
GNA11	Other/Unknown	no		Gprotein_alpha_Q, Gprotein_alpha_su, GproteinA_insert

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
ileal mucosa	1
jejunal mucosa	1
pancreatic ductal cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GNA11	299	ubiquitous	marker	ileal mucosa, jejunal mucosa, pancreatic ductal cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GNA11	1,873

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNA11	P29992	13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion	1	1427.5×	0.004	GNA11
Acetylcholine regulates insulin secretion	1	1142.0×	0.004	GNA11
G-protein activation	1	475.8×	0.004	GNA11
Thromboxane signalling through TP receptor	1	475.8×	0.004	GNA11
ADP signalling through P2Y purinoceptor 1	1	456.8×	0.004	GNA11
Thrombin signalling through proteinase activated receptors (PARs)	1	356.9×	0.004	GNA11
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	356.9×	0.004	GNA11
Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding	1	300.5×	0.005	GNA11
PLC beta mediated events	1	265.6×	0.005	GNA11
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	160.8×	0.007	GNA11
G alpha (q) signalling events	1	57.4×	0.017	GNA11

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
regulation of melanocyte differentiation	1	16852.0×	0.001	GNA11
entrainment of circadian clock	1	2808.7×	0.001	GNA11
phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway	1	2106.5×	0.001	GNA11
developmental pigmentation	1	2106.5×	0.001	GNA11
phospholipase C-activating dopamine receptor signaling pathway	1	2106.5×	0.001	GNA11
cellular response to pH	1	2106.5×	0.001	GNA11
ligand-gated ion channel signaling pathway	1	1872.4×	0.001	GNA11
endothelin receptor signaling pathway	1	1685.2×	0.001	GNA11
phototransduction, visible light	1	1296.3×	0.002	GNA11
G protein-coupled acetylcholine receptor signaling pathway	1	1053.2×	0.002	GNA11
cranial skeletal system development	1	936.2×	0.002	GNA11
action potential	1	358.6×	0.004	GNA11
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1	337.0×	0.004	GNA11
positive regulation of insulin secretion	1	255.3×	0.005	GNA11
regulation of blood pressure	1	221.7×	0.006	GNA11
phospholipase C-activating G protein-coupled receptor signaling pathway	1	131.7×	0.009	GNA11
skeletal system development	1	125.8×	0.009	GNA11
heart development	1	78.8×	0.013	GNA11
signal transduction	1	16.1×	0.062	GNA11

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
GNA11	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
GNA11	18	Binding:18

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	GNA11

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)
GNA11	18	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.