Tumoral calcinosis, hyperphosphatemic, familial, 1

Summary

Tumoral calcinosis, hyperphosphatemic, familial, 1 (MONDO:0100252) is a disease caused by GALNT3 (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: GALNT3 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 155

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	tumoral calcinosis, hyperphosphatemic, familial, 1
Mondo ID	MONDO:0100252
OMIM	211900
UMLS	C4692564
MedGen	1642611
GARD	0015146
Is cancer (heuristic)	no

Also known as: calcinosis, tumoral, with hyperphosphatemia · HFTC · HFTC1 · hyperostosis-hyperphosphatemia syndrome · Morbus Teutschlaender · Teutschlaender disease, familial · tumoral calcinosis, hyperphosphatemic, familial · tumoral calcinosis, HYPERPHOSPHATEMIC, familial, 1 · tumoral calcinosis, Hyperphosphatemic, familial, 1 · tumoral calcinosis, hyperphosphatemic, familial, 1 · tumoral calcinosis, primary Hyperphosphatemic

Data availability: 155 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, 1

Related subtypes (4): normophosphatemic familial tumoral calcinosis, tumoral calcinosis, hyperphosphatemic, familial, 2, tumoral calcinosis, hyperphosphatemic, familial, 3, familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome

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

155 retrieved; paginated sample, class counts are floors:

88 uncertain significance, 19 pathogenic, 13 conflicting classifications of pathogenicity, 10 likely pathogenic, 9 benign, 8 pathogenic/likely pathogenic, 5 benign/likely benign, 2 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
444061	NM_020638.3(FGF23):c.385T>C (p.Ser129Pro)	FGF23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
444062	NM_020638.3(FGF23):c.367G>T (p.Gly123Trp)	FGF23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1403790	NM_004482.4(GALNT3):c.1312C>T (p.Arg438Cys)	GALNT3	Pathogenic	criteria provided, multiple submitters, no conflicts
1418978	NM_004482.4(GALNT3):c.985G>A (p.Gly329Arg)	GALNT3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2192673	NM_004482.4(GALNT3):c.1696C>T (p.Gln566Ter)	GALNT3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2203165	NM_004482.4(GALNT3):c.746_749del (p.Val249fs)	GALNT3	Pathogenic	criteria provided, multiple submitters, no conflicts
2637478	NM_004482.4(GALNT3):c.516-2A>G	GALNT3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2734290	NM_004482.4(GALNT3):c.1102dup (p.Ser368fs)	GALNT3	Pathogenic	criteria provided, multiple submitters, no conflicts
2734293	NM_004482.4(GALNT3):c.260_266del (p.Arg87fs)	GALNT3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2991659	NM_004482.4(GALNT3):c.149C>G (p.Ser50Ter)	GALNT3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3383236	NM_004482.4(GALNT3):c.220A>T (p.Lys74Ter)	GALNT3	Pathogenic	criteria provided, single submitter
4277847	NM_004482.4(GALNT3):c.1688A>C (p.His563Pro)	GALNT3	Pathogenic	criteria provided, single submitter
497358	NM_004482.4(GALNT3):c.892del (p.Tyr298fs)	GALNT3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
561015	NM_004482.4(GALNT3):c.505C>T (p.Arg169Ter)	GALNT3	Pathogenic	criteria provided, multiple submitters, no conflicts
7791	NM_004482.4(GALNT3):c.1524+1G>A	GALNT3	Pathogenic	criteria provided, multiple submitters, no conflicts
7792	NM_004482.4(GALNT3):c.484C>T (p.Arg162Ter)	GALNT3	Pathogenic	criteria provided, multiple submitters, no conflicts
7793	NM_004482.4(GALNT3):c.1524+5G>A	GALNT3	Pathogenic	criteria provided, multiple submitters, no conflicts
7794	NM_004482.4(GALNT3):c.516-2A>T	GALNT3	Pathogenic	criteria provided, multiple submitters, no conflicts
7795	NM_004482.4(GALNT3):c.1774C>T (p.Gln592Ter)	GALNT3	Pathogenic	no assertion criteria provided
7796	NM_004482.4(GALNT3):c.1076C>A (p.Thr359Lys)	GALNT3	Pathogenic	no assertion criteria provided
7797	NM_004482.4(GALNT3):c.966T>G (p.Tyr322Ter)	GALNT3	Pathogenic	no assertion criteria provided
7798	NM_004482.4(GALNT3):c.1441C>T (p.Gln481Ter)	GALNT3	Pathogenic	no assertion criteria provided
7799	NM_004482.4(GALNT3):c.815C>A (p.Thr272Lys)	GALNT3	Pathogenic	no assertion criteria provided
7800	NM_004482.4(GALNT3):c.803dup (p.Thr269fs)	GALNT3	Pathogenic	criteria provided, multiple submitters, no conflicts
7801	NM_004482.4(GALNT3):c.1626+1G>A	GALNT3	Pathogenic	criteria provided, multiple submitters, no conflicts
7802	NM_004482.4(GALNT3):c.677del (p.Ala226fs)	GALNT3	Pathogenic	no assertion criteria provided
7803	NM_004482.4(GALNT3):c.1720T>G (p.Cys574Gly)	GALNT3	Pathogenic	no assertion criteria provided
2780010	NM_004482.4(GALNT3):c.1681T>A (p.Cys561Ser)	GALNT3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2796073	NM_004482.4(GALNT3):c.1074-1G>C	GALNT3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2834157	NM_004482.4(GALNT3):c.689-2A>G	GALNT3	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 4 · 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
GALNT3	Definitive	Autosomal recessive	tumoral calcinosis, hyperphosphatemic, familial, 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GALNT3	Orphanet:306661	Familial hyperphosphatemic tumoral calcinosis/Hyperphosphatemic hyperostosis syndrome
FGF23	Orphanet:306661	Familial hyperphosphatemic tumoral calcinosis/Hyperphosphatemic hyperostosis syndrome
FGF23	Orphanet:89937	Autosomal dominant hypophosphatemic rickets
KL	Orphanet:306661	Familial hyperphosphatemic tumoral calcinosis/Hyperphosphatemic hyperostosis syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GALNT3	HGNC:4125	ENSG00000115339	Q14435	Polypeptide N-acetylgalactosaminyltransferase 3	gencc,clinvar
A2ML1	HGNC:23336	ENSG00000166535	A8K2U0	Alpha-2-macroglobulin-like protein 1	clinvar
FGF23	HGNC:3680	ENSG00000118972	Q9GZV9	Fibroblast growth factor 23	clinvar
KL	HGNC:6344	ENSG00000133116	Q9UEF7	Klotho	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GALNT3	Polypeptide N-acetylgalactosaminyltransferase 3	Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor.
A2ML1	Alpha-2-macroglobulin-like protein 1	Is able to inhibit all four classes of proteinases by a unique ’trapping’ mechanism.
FGF23	Fibroblast growth factor 23	Regulator of phosphate homeostasis.
KL	Klotho	May have weak glycosidase activity towards glucuronylated steroids.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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
Complement	1	67.0×	0.045
Enzyme (other)	1	3.0×	0.441
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GALNT3	Enzyme (other)	yes	2.4.1.41	Ricin_B_lectin, Glyco_trans_2-like, Nucleotide-diphossugar_trans
A2ML1	Complement	yes		Macroglobln_a2, MG2, Terpenoid_cyclase/PrenylTrfase
FGF23	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF
KL	Other/Unknown	no		Glyco_hydro_1, GH_hydrolase_sf, GH_1_N_CS

Expression context

Cohort genes with no expression data: 0.

4 cohort genes 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	1
mucosa of sigmoid colon	1
parotid gland	1
gingiva	1
gingival epithelium	1
lower esophagus mucosa	1
hair follicle	1
primordial germ cell in gonad	1
sural nerve	1
choroid plexus epithelium	1
kidney epithelium	1
nephron tubule	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GALNT3	234	ubiquitous	marker	mucosa of sigmoid colon, bronchial epithelial cell, parotid gland
A2ML1	176	tissue_specific	marker	lower esophagus mucosa, gingiva, gingival epithelium
FGF23	44	tissue_specific	marker	sural nerve, primordial germ cell in gonad, hair follicle
KL	188	tissue_specific	marker	choroid plexus epithelium, nephron tubule, kidney epithelium

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FGF23	1,533
KL	1,494
GALNT3	1,196
A2ML1	1,128

Intra-cohort edges

A	B	Sources
FGF23	GALNT3	string_interaction
FGF23	KL	biogrid_interaction, string_interaction
GALNT3	KL	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGF23	Q9GZV9	6
KL	Q9UEF7	6
A2ML1	A8K2U0	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GALNT3	Q14435	89.88

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 42. Enrichment computed across 4 evidence-associated genes (3 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 3 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	2	1903.3×	1e-05	FGF23, KL
FGFR3c ligand binding and activation	2	585.6×	8e-05	GALNT3, FGF23
Phospholipase C-mediated cascade: FGFR1	2	447.8×	8e-05	FGF23, KL
Downstream signaling of activated FGFR1	2	362.5×	8e-05	FGF23, KL
PI-3K cascade:FGFR1	2	346.1×	8e-05	FGF23, KL
SHC-mediated cascade:FGFR1	2	331.0×	8e-05	FGF23, KL
FRS-mediated FGFR1 signaling	2	304.5×	8e-05	FGF23, KL
Negative regulation of FGFR1 signaling	2	245.6×	1e-04	FGF23, KL
PI3K Cascade	2	181.3×	2e-04	FGF23, KL
Constitutive Signaling by Aberrant PI3K in Cancer	2	84.6×	8e-04	FGF23, KL
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	2	64.5×	0.001	FGF23, KL
PIP3 activates AKT signaling	2	44.5×	0.002	FGF23, KL
RAF/MAP kinase cascade	2	40.7×	0.003	FGF23, KL
Signaling by activated point mutants of FGFR1	1	317.2×	0.008	FGF23
Signaling by activated point mutants of FGFR3	1	317.2×	0.008	FGF23
FGFR2c ligand binding and activation	1	292.8×	0.008	FGF23
Phospholipase C-mediated cascade; FGFR3	1	292.8×	0.008	FGF23
FGFRL1 modulation of FGFR1 signaling	1	292.8×	0.008	FGF23
FGFR4 ligand binding and activation	1	271.9×	0.008	FGF23
FGFR1c ligand binding and activation	1	253.8×	0.008	FGF23
Phospholipase C-mediated cascade; FGFR4	1	253.8×	0.008	FGF23
Defective GALNT3 causes HFTC	1	237.9×	0.008	GALNT3
Activated point mutants of FGFR2	1	223.9×	0.008	FGF23
Phospholipase C-mediated cascade; FGFR2	1	211.5×	0.008	FGF23
PI-3K cascade:FGFR3	1	211.5×	0.008	FGF23
SHC-mediated cascade:FGFR3	1	200.3×	0.008	FGF23
PI-3K cascade:FGFR4	1	190.3×	0.008	FGF23
FRS-mediated FGFR3 signaling	1	181.3×	0.008	FGF23
SHC-mediated cascade:FGFR4	1	181.3×	0.008	FGF23
PI-3K cascade:FGFR2	1	165.5×	0.008	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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
fibroblast growth factor receptor signaling pathway	3	214.2×	7e-06	GALNT3, FGF23, KL
positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway	2	1404.3×	1e-05	FGF23, KL
calcium ion homeostasis	2	221.7×	5e-04	FGF23, KL
obsolete positive regulation of vitamin D 24-hydroxylase activity	1	4213.0×	0.002	FGF23
regulation of endopeptidase activity	1	4213.0×	0.002	A2ML1
polysaccharide metabolic process	1	1404.3×	0.005	GALNT3
regulation of phosphate transport	1	1404.3×	0.005	FGF23
vitamin D catabolic process	1	1053.2×	0.005	FGF23
norepinephrine biosynthetic process	1	526.6×	0.008	KL
negative regulation of hormone secretion	1	468.1×	0.008	FGF23
response to angiotensin	1	468.1×	0.008	KL
response to sodium phosphate	1	421.3×	0.008	FGF23
intracellular phosphate ion homeostasis	1	383.0×	0.008	FGF23
cellular response to leptin stimulus	1	383.0×	0.008	FGF23
cellular response to vitamin D	1	383.0×	0.008	FGF23
response to magnesium ion	1	351.1×	0.008	FGF23
cellular response to parathyroid hormone stimulus	1	351.1×	0.008	FGF23
negative regulation of systemic arterial blood pressure	1	263.3×	0.009	KL
energy reserve metabolic process	1	263.3×	0.009	KL
phosphate ion homeostasis	1	263.3×	0.009	FGF23
cellular response to interleukin-6	1	247.8×	0.009	FGF23
chondrocyte development	1	234.1×	0.009	GALNT3
negative regulation of bone mineralization	1	234.1×	0.009	FGF23
response to vitamin D	1	200.6×	0.010	KL
chondroitin sulfate proteoglycan biosynthetic process	1	156.0×	0.012	GALNT3
endochondral ossification	1	135.9×	0.013	GALNT3
cell maturation	1	110.9×	0.015	GALNT3
determination of adult lifespan	1	108.0×	0.015	KL
protein O-linked glycosylation via N-acetylgalactosamine	1	108.0×	0.015	GALNT3
limb development	1	102.8×	0.015	GALNT3

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GALNT3	0	0
A2ML1	0	0
FGF23	0	0
KL	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
FGF23	2	Binding:2
GALNT3	1	Binding:1
KL	1	ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GALNT3	2.4.1.41	polypeptide N-acetylgalactosaminyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	1	A2ML1
D	Druggable family + AlphaFold only, no drug	1	GALNT3
E	Difficult family or no structure, no drug	2	FGF23, KL

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
GALNT3	1	—
A2ML1	0	—
FGF23	2	—
KL	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.