Tumoral calcinosis, hyperphosphatemic, familial, 2

Summary

Tumoral calcinosis, hyperphosphatemic, familial, 2 (MONDO:0060714) is a disease caused by FGF23 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: FGF23 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 100

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	tumoral calcinosis, hyperphosphatemic, familial, 2
Mondo ID	MONDO:0060714
EFO	EFO:0009383
OMIM	617993
UMLS	C4693863
MedGen	1640532
GARD	0016281
Is cancer (heuristic)	no

Also known as: HFTC2 · tumoral calcinosis, hyperphosphatemic, familial, 2

Data availability: 100 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › familial tumoral calcinosis › tumoral calcinosis, hyperphosphatemic, familial, 2

Related subtypes (4): normophosphatemic familial tumoral calcinosis, tumoral calcinosis, hyperphosphatemic, familial, 3, familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome, tumoral calcinosis, hyperphosphatemic, familial, 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

100 retrieved; paginated sample, class counts are floors:

58 uncertain significance, 13 conflicting classifications of pathogenicity, 11 benign, 8 benign/likely benign, 4 pathogenic, 4 likely benign, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1179114	GRCh37/hg19 12p13.32(chr12:4477393-4488878)	FGF23	Pathogenic	no assertion criteria provided
36135	NM_020638.3(FGF23):c.536G>A (p.Arg179Gln)	FGF23	Pathogenic	criteria provided, multiple submitters, no conflicts
444061	NM_020638.3(FGF23):c.385T>C (p.Ser129Pro)	FGF23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5028	NM_020638.3(FGF23):c.287T>C (p.Met96Thr)	FGF23	Pathogenic	no assertion criteria provided
5029	NM_020638.3(FGF23):c.386C>T (p.Ser129Phe)	FGF23	Pathogenic	no assertion criteria provided
3574584	NM_020638.3(FGF23):c.211+1G>A	FGF23	Likely pathogenic	criteria provided, single submitter
1427539	NM_020638.3(FGF23):c.559C>G (p.Arg187Gly)	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308775	NM_020638.3(FGF23):c.*1886C>A	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308776	NM_020638.3(FGF23):c.*1803C>T	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308777	NM_020638.3(FGF23):c.*1772G>A	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308805	NM_020638.3(FGF23):c.551A>G (p.Asp184Gly)	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308806	NM_020638.3(FGF23):c.515C>T (p.Pro172Leu)	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
308807	NM_020638.3(FGF23):c.331G>A (p.Glu111Lys)	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
5027	NM_020638.3(FGF23):c.211A>G (p.Ser71Gly)	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880634	NM_020638.3(FGF23):c.*1398T>A	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
882110	NM_020638.3(FGF23):c.*235C>T	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
882162	NM_020638.3(FGF23):c.249G>A (p.Val83=)	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
882164	NM_020638.3(FGF23):c.138A>G (p.Thr46=)	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
930793	NM_020638.3(FGF23):c.88C>T (p.Pro30Ser)	FGF23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1025781	NM_020638.3(FGF23):c.64C>T (p.Leu22Phe)	FGF23	Uncertain significance	criteria provided, multiple submitters, no conflicts
1049194	NM_020638.3(FGF23):c.673G>A (p.Gly225Arg)	FGF23	Uncertain significance	criteria provided, single submitter
1406065	NM_020638.3(FGF23):c.686G>A (p.Gly229Asp)	FGF23	Uncertain significance	criteria provided, multiple submitters, no conflicts
1419246	NM_020638.3(FGF23):c.559C>T (p.Arg187Trp)	FGF23	Uncertain significance	criteria provided, multiple submitters, no conflicts
1472123	NM_020638.3(FGF23):c.46G>A (p.Val16Ile)	FGF23	Uncertain significance	criteria provided, multiple submitters, no conflicts
1504076	NM_020638.3(FGF23):c.636C>A (p.Ser212Arg)	FGF23	Uncertain significance	criteria provided, multiple submitters, no conflicts
1505152	NM_020638.3(FGF23):c.313T>A (p.Ser105Thr)	FGF23	Uncertain significance	criteria provided, multiple submitters, no conflicts
1950107	NM_020638.3(FGF23):c.706G>C (p.Ala236Pro)	FGF23	Uncertain significance	criteria provided, multiple submitters, no conflicts
1986419	NM_020638.3(FGF23):c.550G>A (p.Asp184Asn)	FGF23	Uncertain significance	criteria provided, multiple submitters, no conflicts
2080919	NM_020638.3(FGF23):c.725A>G (p.Glu242Gly)	FGF23	Uncertain significance	criteria provided, multiple submitters, no conflicts
2418171	NM_020638.3(FGF23):c.277T>C (p.Tyr93His)	FGF23	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · 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
FGF23	Strong	Autosomal recessive	tumoral calcinosis, hyperphosphatemic, familial, 2	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FGF23	Orphanet:306661	Familial hyperphosphatemic tumoral calcinosis/Hyperphosphatemic hyperostosis syndrome
FGF23	Orphanet:89937	Autosomal dominant hypophosphatemic rickets

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
FGF23	HGNC:3680	ENSG00000118972	Q9GZV9	Fibroblast growth factor 23	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FGF23	Fibroblast growth factor 23	Regulator of phosphate homeostasis.

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)
FGF23	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF

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
hair follicle	1
primordial germ cell in gonad	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FGF23	44	tissue_specific	marker	sural nerve, primordial germ cell in gonad, hair follicle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGF23	1,533

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGF23	Q9GZV9	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 40. 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
FGFR1c and Klotho ligand binding and activation	1	2855.0×	0.003	FGF23
Signaling by activated point mutants of FGFR1	1	951.7×	0.003	FGF23
Signaling by activated point mutants of FGFR3	1	951.7×	0.003	FGF23
FGFR3c ligand binding and activation	1	878.5×	0.003	FGF23
FGFR2c ligand binding and activation	1	878.5×	0.003	FGF23
Phospholipase C-mediated cascade; FGFR3	1	878.5×	0.003	FGF23
FGFRL1 modulation of FGFR1 signaling	1	878.5×	0.003	FGF23
FGFR4 ligand binding and activation	1	815.7×	0.003	FGF23
FGFR1c ligand binding and activation	1	761.3×	0.003	FGF23
Phospholipase C-mediated cascade; FGFR4	1	761.3×	0.003	FGF23
Activated point mutants of FGFR2	1	671.8×	0.003	FGF23
Phospholipase C-mediated cascade: FGFR1	1	671.8×	0.003	FGF23
Phospholipase C-mediated cascade; FGFR2	1	634.4×	0.003	FGF23
PI-3K cascade:FGFR3	1	634.4×	0.003	FGF23
SHC-mediated cascade:FGFR3	1	601.0×	0.003	FGF23
PI-3K cascade:FGFR4	1	571.0×	0.003	FGF23
Downstream signaling of activated FGFR1	1	543.8×	0.003	FGF23
FRS-mediated FGFR3 signaling	1	543.8×	0.003	FGF23
SHC-mediated cascade:FGFR4	1	543.8×	0.003	FGF23
PI-3K cascade:FGFR1	1	519.1×	0.003	FGF23
SHC-mediated cascade:FGFR1	1	496.5×	0.003	FGF23
PI-3K cascade:FGFR2	1	496.5×	0.003	FGF23
FRS-mediated FGFR4 signaling	1	496.5×	0.003	FGF23
Signaling by FGFR3 in disease	1	496.5×	0.003	FGF23
SHC-mediated cascade:FGFR2	1	475.8×	0.003	FGF23
FRS-mediated FGFR1 signaling	1	456.8×	0.003	FGF23
FRS-mediated FGFR2 signaling	1	439.2×	0.003	FGF23
Negative regulation of FGFR3 signaling	1	439.2×	0.003	FGF23
Negative regulation of FGFR4 signaling	1	407.9×	0.003	FGF23
Negative regulation of FGFR1 signaling	1	368.4×	0.004	FGF23

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
obsolete positive regulation of vitamin D 24-hydroxylase activity	1	16852.0×	0.001	FGF23
regulation of phosphate transport	1	5617.3×	0.002	FGF23
vitamin D catabolic process	1	4213.0×	0.002	FGF23
positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway	1	2808.7×	0.002	FGF23
negative regulation of hormone secretion	1	1872.4×	0.002	FGF23
response to sodium phosphate	1	1685.2×	0.002	FGF23
intracellular phosphate ion homeostasis	1	1532.0×	0.002	FGF23
cellular response to leptin stimulus	1	1532.0×	0.002	FGF23
cellular response to vitamin D	1	1532.0×	0.002	FGF23
response to magnesium ion	1	1404.3×	0.002	FGF23
cellular response to parathyroid hormone stimulus	1	1404.3×	0.002	FGF23
phosphate ion homeostasis	1	1053.2×	0.002	FGF23
cellular response to interleukin-6	1	991.3×	0.002	FGF23
negative regulation of bone mineralization	1	936.2×	0.002	FGF23
calcium ion homeostasis	1	443.5×	0.004	FGF23
ERK1 and ERK2 cascade	1	318.0×	0.005	FGF23
negative regulation of osteoblast differentiation	1	295.6×	0.005	FGF23
fibroblast growth factor receptor signaling pathway	1	285.6×	0.005	FGF23
neurogenesis	1	208.1×	0.006	FGF23
regulation of cell migration	1	157.5×	0.008	FGF23
positive regulation of ERK1 and ERK2 cascade	1	85.1×	0.013	FGF23
positive regulation of MAPK cascade	1	80.6×	0.014	FGF23
positive regulation of cell population proliferation	1	33.6×	0.031	FGF23
positive regulation of DNA-templated transcription	1	27.9×	0.036	FGF23

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
FGF23	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
FGF23	2	Binding:2

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	FGF23

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)
FGF23	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.