FAM20C

Summary

FAM20C (FAM20C golgi associated secretory pathway kinase, HGNC:22140) is a protein-coding gene on chromosome 7p22.3, encoding Extracellular serine/threonine protein kinase FAM20C (Q8IXL6). Golgi serine/threonine protein kinase that phosphorylates secretory pathway proteins within Ser-x-Glu/pSer motifs and plays a key role in biomineralization of bones and teeth.

This gene encodes a member of the family of secreted protein kinases. The encoded protein binds calcium and phosphorylates proteins involved in bone mineralization. Mutations in this gene are associated with the autosomal recessive disorder Raine syndrome.

Source: NCBI Gene 56975 — RefSeq curated summary.

At a glance

• Gene–disease (curated): lethal osteosclerotic bone dysplasia (Definitive, ClinGen)
• GWAS associations: 2
• Clinical variants (ClinVar): 598 total — 22 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 65
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_020223

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:22140
Approved symbol	FAM20C
Name	FAM20C golgi associated secretory pathway kinase
Location	7p22.3
Locus type	gene with protein product
Status	Approved
Aliases	IMAGE:4942737, DKFZp547D065, DMP4, G-CK
Ensembl gene	ENSG00000177706
Ensembl biotype	protein_coding
OMIM	611061
Entrez	56975

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding, 2 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000313766, ENST00000471328, ENST00000477004, ENST00000512382, ENST00000515795, ENST00000866115, ENST00000866116, ENST00000920763, ENST00000942064, ENST00000942065, ENST00000942066, ENST00000942067

RefSeq mRNA: 1 — MANE Select: NM_020223 NM_020223

CCDS: CCDS47522

Canonical transcript exons

ENST00000313766 — 10 exons

Exon	Start	End
ENSE00001232590	192571	193804
ENSE00001604195	246415	246507
ENSE00003464110	195554	195732
ENSE00003483577	258646	258705
ENSE00003549430	255849	256029
ENSE00003549954	257005	257086
ENSE00003585143	248315	248430
ENSE00003643858	259731	260772
ENSE00003659676	256654	256763
ENSE00003661949	208898	208976

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 96.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.1015 / max 468.2337, expressed in 1530 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76845	23.3932	1507
76842	1.7845	682
76840	1.2198	815
76841	0.3499	193
76843	0.1849	73
76846	0.1126	39
76844	0.0566	20

Top tissues by expression

134 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	96.57	gold quality
adult mammalian kidney	UBERON:0000082	96.00	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.73	gold quality
lower esophagus	UBERON:0013473	95.70	gold quality
body of stomach	UBERON:0001161	94.94	gold quality
ascending aorta	UBERON:0001496	94.77	gold quality
descending thoracic aorta	UBERON:0002345	94.73	gold quality
thoracic aorta	UBERON:0001515	94.71	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.70	gold quality
popliteal artery	UBERON:0002250	94.35	gold quality
tibial artery	UBERON:0007610	94.33	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.15	gold quality
liver	UBERON:0002107	94.14	gold quality
right coronary artery	UBERON:0001625	94.08	gold quality
left coronary artery	UBERON:0001626	94.00	gold quality
metanephros cortex	UBERON:0010533	93.95	gold quality
fundus of stomach	UBERON:0001160	93.75	gold quality
stomach	UBERON:0000945	93.15	gold quality
tibial nerve	UBERON:0001323	93.08	gold quality
prostate gland	UBERON:0002367	92.94	gold quality
thoracic mammary gland	UBERON:0005200	92.88	gold quality
omental fat pad	UBERON:0010414	92.80	gold quality
vermiform appendix	UBERON:0001154	92.75	gold quality
adipose tissue	UBERON:0001013	92.51	gold quality
kidney	UBERON:0002113	92.48	gold quality
subcutaneous adipose tissue	UBERON:0002190	92.29	gold quality
right atrium auricular region	UBERON:0006631	92.08	gold quality
mucosa of stomach	UBERON:0001199	91.85	gold quality
urinary bladder	UBERON:0001255	91.71	gold quality
right ovary	UBERON:0002118	91.69	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.02

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

33 targeting FAM20C, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-10393-5P	99.65	68.01	1368
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-4452	99.50	68.45	1493
HSA-MIR-4325	99.49	72.20	1342
HSA-MIR-4680-3P	98.64	68.60	2093
HSA-MIR-6731-3P	98.61	67.86	749
HSA-MIR-4718	98.55	68.61	814
HSA-MIR-5008-5P	98.42	65.87	1019
HSA-MIR-653-3P	98.31	67.71	1542
HSA-MIR-7703	97.64	67.00	965
HSA-MIR-4642	97.52	67.60	916
HSA-MIR-6791-3P	97.45	64.31	1123
HSA-MIR-6829-3P	97.45	64.31	1137
HSA-MIR-6734-5P	95.70	65.56	950
HSA-MIR-769-5P	94.45	64.56	603

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 38)

• This study defines the causative role of FAM20C in this lethal osteosclerotic disorder and its crucial role in normal bone development. (PMID:17924334)
• Mutation of FAM20C does not always lead to the infantile lethality previously seen as a prerequisite for Raine syndrome diagnosis. (PMID:19250384)
• Osteosclerotic bone dysplasia in siblings with a Fam20C mutation (PMID:20825432)
• Fam20C appears to be the Golgi casein kinase that phosphorylates secretory pathway proteins within S-x-E motifs; Fam20C phosphorylates caseins and several secreted proteins implicated in biomineralization; mutations in Fam20C cause an osteosclerotic bone dysplasia known as Raine syndrome (PMID:22582013)
• Our results identify FAM20C as a kinase for secreted phosphoproteins and establish a biochemical basis for Raine syndrome. (PMID:22900076)
• mutations in FAM20C provide a putative new mechanism in human subjects leading to dysregulated FGF23 levels, hypophosphatemia, hyperphosphaturia, dental anomalies, intracerebral calcifications and osteosclerosis of the long bones (PMID:23325605)
• We report on a child who is homozygous for a 487-kb deletion in 7p22.3 that contains FAM20C (PMID:24039075)
• Fam20C phosphorylates FGF23, which promotes FGF23 proteolysis by furin by blocking O-glycosylation by polypeptide N-acetylgalactosaminyltransferase 3. (PMID:24706917)
• Findings suggest that certain homozygous FAM20C mutations can cause FGF23-related hypophosphatemic osteomalacia and indicate the multiple roles of FAM20C in bone. (PMID:24982027)
• Results suggest that FAM20C suppresses FGF23 production by enhancing DMP1 expression, and inactivating mutations in FAM20C cause FGF23-related hypophosphatemia by decreasing transcription of DMP1. (PMID:25026495)
• Fam20A potentiates Fam20C kinase activity and promotes the phosphorylation of enamel matrix proteins in vitro. (PMID:25789606)
• The Fam20C-and VLK-family of kinases mediate the phosphorylation of proteins in the secretory pathway and extracellular space.Mutation in several secretory pathway kinases cause human disease (PMID:25862977)
• phenotype in two families with non-lethal Raine syndrome with FAM20C mutations (PMID:25928877)
• by treating Fam20C expressing HEK293T cells with myriocin, a potent inhibitor of the sphingosine biosynthetic pathway, the activity of Fam20C released into the conditioned medium is substantially decreased corroborating the concept that sphingosine (PMID:25936777)
• Using CRISPR/Cas9 genome editing, mass spectrometry, and biochemistry, study identifies more than 100 secreted phosphoproteins as genuine Fam20C substrates; further, study shows that Fam20C exhibits broader substrate specificity than previously appreciated. (PMID:26091039)
• Our report reinforces that Raine syndrome is compatible with life, and that mild hypophosphatemia and amelogenesis imperfecta are key features of the attenuated form. (PMID:27667191)
• findings clarify FAM20C’s role in hard tissue formation and mineralization, and show that Raine syndrome is congenital sclerosing osteomalacia with cerebral calcification. (PMID:27862258)
• Alterations of Fam20C activity, promoted by myriocin and sphingolipids, are not accompanied by any significant change in Fam20C protein. These data provide the proof of concept that Fam20C activity is under the control of sphingolipid signaling (PMID:28236661)
• Histidine-rich Ca-binding protein (HRC) was phosphorylated by family with sequence similarity 20C (Fam20C) both in vitro and in vivo. (PMID:28784772)
• that FAM20C may affect the biomineralization by the means more than local phosphorylation of extracellular matrix proteins and systemic phosphorus homeostasis (PMID:28926103)
• These results suggest that TET1 potentially promotes the cytodifferentiation potential of human dental pulp cells through its DNA demethylation machinery and upregulation of FAM20C protein expression. (PMID:29277934)
• Study identified a homozygous missense variant c.1228 T > A (p.Ser410Thr) in the exon 6 of FAM20C gene. This mutation is likely pathogenic variant that confirmed the clinical diagnosis of Raine syndrome. (PMID:29751744)
• The authors show that endoplasmic reticulum oxidoreductin 1alpha (Ero1alpha), the pivotal sulfhydryl oxidase that catalyzes disulfide formation in the endoplasmic reticulum, is phosphorylated by Fam20C in the Golgi apparatus and retrograde-transported to the endoplasmic reticulum mediated by ERp44. (PMID:29858230)
• FAM20c phosphorylated purified plasma VWF, VWF A1A2A3 protein, isolated A2 domain, but not A1 and A3 domain proteins, in vitro. FAM20c phosphorylated the isolated A2 domain at S1517 and S1613 within the S-X-E recognition motif, with S1613 being the major phosphorylation site. (PMID:30864273)
• The clinical presentation was highly suggestive of Raine syndrome. A homozygous, novel missense variant in exon 5 of FAM20C (c.1007T>G; p.Met336Arg) was identified by targeted Sanger sequencing. (PMID:31297960)
• Two Novel FAM20C Variants in A Family with Raine Syndrome. (PMID:32093234)
• Phosphorylation switches protein disulfide isomerase activity to maintain proteostasis and attenuate ER stress. (PMID:32149426)
• Adult diffuse glioma GWAS by molecular subtype identifies variants in D2HGDH and FAM20C. (PMID:32386320)
• Fam20C regulates protein secretion by Cab45 phosphorylation. (PMID:32422653)
• Ras-transformation reduce FAM20C expression and osteopontin phosphorylation. (PMID:32830861)
• FAM20C directly binds to and phosphorylates Periostin. (PMID:33051588)
• Prognostic and immunological role of Fam20C in pan-cancer. (PMID:33306121)
• The ABCs of the atypical Fam20 secretory pathway kinases. (PMID:33759783)
• Proteolytic processing of secretory pathway kinase Fam20C by site-1 protease promotes biomineralization. (PMID:34349020)
• FAM20C Overview: Classic and Novel Targets, Pathogenic Variants and Raine Syndrome Phenotypes. (PMID:34360805)
• Fam20C Regulates Bone Resorption and Breast Cancer Bone Metastasis through Osteopontin and BMP4. (PMID:34433585)
• Epigenetic and transcriptional activation of the secretory kinase FAM20C as an oncogene in glioma. (PMID:36708808)
• Intracranial calcification in Fam20c-deficient mice recapitulates human Raine syndrome. (PMID:36914045)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	fam20ca	ENSDARG00000074317
danio_rerio	fam20cb	ENSDARG00000090338
mus_musculus	Fam20c	ENSMUSG00000025854
rattus_norvegicus	Fam20c	ENSRNOG00000001314
drosophila_melanogaster	CG31145	FBGN0051145
caenorhabditis_elegans		WBGENE00010356

Paralogs (2): FAM20A (ENSG00000108950), FAM20B (ENSG00000116199)

Protein

Protein identifiers

Extracellular serine/threonine protein kinase FAM20C — Q8IXL6 (reviewed: Q8IXL6)

Alternative names: Dentin matrix protein 4, Golgi casein kinase, Golgi-enriched fraction casein kinase

All UniProt accessions (1): Q8IXL6

UniProt curated annotations — full annotation on UniProt →

Function. Golgi serine/threonine protein kinase that phosphorylates secretory pathway proteins within Ser-x-Glu/pSer motifs and plays a key role in biomineralization of bones and teeth. Constitutes the main protein kinase for extracellular proteins, generating the majority of the extracellular phosphoproteome. Mainly phosphorylates proteins within the Ser-x-Glu/pSer motif, but also displays a broader substrate specificity. Phosphorylates ERO1A, enhancing its activity which is required to maintain endoplasmic reticulum redox homeostasis and for oxidative protein folding. During endoplasmic reticulum stress, phosphorylates P4HB/PDIA1 which induces a functional switch, causing P4HB to change from an oxidoreductase to a molecular chaperone. This is critical to maintain ER proteostasis and reduce cell death under ER stress. Phosphorylation of P4HB also promotes its interaction with ERN1, leading to reduced activity of ERN1, a key sensor for the endoplasmic reticulum unfolded protein response. Required for osteoblast differentiation and mineralization. Phosphorylates casein as well as a number of proteins involved in biomineralization such as AMELX, AMTN, ENAM and SPP1/OPN. In addition to its role in biomineralization, also plays a role in lipid homeostasis, wound healing and cell migration and adhesion.

Subunit / interactions. Homodimer; disulfide-linked. Interacts with FAM20A; probably forming a heterotetramer of 2 subunits of FAM20A and 2 subunits of FAM20C. Interacts with protease MBTPS1/S1P; the interaction results in FAM20C cleavage and secretion. Interacts with COPII components SEC23A and SEC24A; transport of FAM20C from the endoplasmic reticulum to the Golgi is likely to be mediated by COPII vesicles.

Subcellular location. Golgi apparatus membrane. Secreted. Endoplasmic reticulum.

Tissue specificity. Widely expressed.

Post-translational modifications. N-glycosylation is required for folding. Autophosphorylated. Propeptide cleavage by MBTPS1/S1P promotes FAM20C secretion and maximal kinase activity which is essential for efficient osteoblast differentiation and biomineralization.

Disease relevance. Raine syndrome (RNS) [MIM:259775] An autosomal recessive osteosclerotic bone dysplasia with neonatal lethal outcome, although some patients survive into childhood. Clinical features include generalized increase in the density of all bones and a marked increase in the ossification of the skull, craniofacial dysplasia and microcephaly. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Serine/threonine protein kinase activity is increased upon interaction with FAM20A.

Similarity. Belongs to the FAM20 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IXL6-1	1	yes
Q8IXL6-2	2

RefSeq proteins (1): NP_064608* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009581	FAM20_C	Domain
IPR024869	FAM20	Family

Pfam: PF06702

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (97 total): mutagenesis site 19, helix 17, strand 11, sequence variant 9, binding site 8, turn 7, disulfide bond 6, compositionally biased region 3, glycosylation site 3, region of interest 3, topological domain 2, sequence conflict 2, propeptide 1, chain 1, active site 1, site 1, modified residue 1, transmembrane region 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5YH3	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IXL6-F1	80.97	0.68

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 458; 92–93 (cleavage; by mbtps1)

Ligand- & substrate-binding residues (8): 269; 285; 306; 306; 389–392; 463; 478; 478

Post-translational modifications (1): 106

Disulfide bonds (6): 46, 48, 362–378, 367–371, 426–500, 501–560

Glycosylation sites (3): 101, 335, 470

Mutagenesis-validated functional residues (19):

Position	Phenotype
28–31	loss of membrane localization with more efficient secretion and loss of propeptide cleavage. reduced oligomerization.
46	no effect on homodimer formation. complete disruption of homodimer formation but no effect on secretion; when associated
48	no effect on homodimer formation. complete disruption of homodimer formation but no effect on secretion; when associated
89	impaired secretion. loss of ability to promote osteoblast differentiation; when associated with a-92.
90	no effect on secretion.
91–93	no effect on secretion or activity.
91	impaired secretion.
92	impaired secretion. loss of ability to promote osteoblast differentiation; when associated with a-89.
101	impaired secretion; when associated with a-335 and a-470.
106	abolishes phosphorylation.
271	reduced kinase activity.
285	reduced kinase activity.
306	strongly reduced kinase activity.
311	reduced kinase activity.
335	impaired secretion; when associated with a-101 and a-470.
408	reduced kinase activity.
458	abrogates kinase activity.
470	impaired secretion; when associated with a-101 and a-335.
478	unable to bind manganese. abrogates kinase activity. loss of ero1a phosphorylation. loss of autophosphorylation. loss of

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-8957275	Post-translational protein phosphorylation

MSigDB gene sets: 337 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_MYELOID_CELL_DEVELOPMENT, GOBP_BONE_CELL_DEVELOPMENT, GOBP_OSTEOBLAST_DIFFERENTIATION, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, HNF1_Q6, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_1, GOBP_TOOTH_MINERALIZATION, chr7p22, COUP_01, GOBP_ANATOMICAL_STRUCTURE_MATURATION, GOBP_ANIMAL_ORGAN_MORPHOGENESIS

GO Biological Process (12): protein phosphorylation (GO:0006468), positive regulation of bone mineralization (GO:0030501), biomineral tissue development (GO:0031214), osteoclast maturation (GO:0036179), regulation of fibroblast growth factor receptor signaling pathway (GO:0040036), post-translational protein modification (GO:0043687), positive regulation of osteoblast differentiation (GO:0045669), regulation of phosphorus metabolic process (GO:0051174), enamel mineralization (GO:0070166), odontoblast differentiation (GO:0071895), dentinogenesis (GO:0097187), skeletal system development (GO:0001501)

GO Molecular Function (12): protease binding (GO:0002020), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), calcium ion binding (GO:0005509), ATP binding (GO:0005524), manganese ion binding (GO:0030145), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (10): Golgi membrane (GO:0000139), obsolete extracellular space (GO:0005615), nucleoplasm (GO:0005654), endoplasmic reticulum lumen (GO:0005788), Golgi apparatus (GO:0005794), extracellular exosome (GO:0070062), extracellular region (GO:0005576), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of proteins	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
protein modification process	2
protein kinase activity	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
phosphorylation	1
bone mineralization	1
regulation of bone mineralization	1
positive regulation of ossification	1
positive regulation of biomineral tissue development	1
tissue development	1
animal organ development	1
osteoclast development	1
cell maturation	1
fibroblast growth factor receptor signaling pathway	1
regulation of signal transduction	1
regulation of cellular response to growth factor stimulus	1
osteoblast differentiation	1
positive regulation of cell differentiation	1
regulation of osteoblast differentiation	1
phosphorus metabolic process	1
regulation of metabolic process	1
tooth mineralization	1
amelogenesis	1
neuroepithelial cell differentiation	1
odontogenesis of dentin-containing tooth	1
anatomical structure formation involved in morphogenesis	1
system development	1
enzyme binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
metal ion binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transition metal ion binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1

Protein interactions and networks

STRING

1232 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FAM20C	MT-ND1	P03886	844
FAM20C	MT-ND5	P03915	817
FAM20C	FAM20A	Q96MK3	801
FAM20C	MT-ND4	P03905	800
FAM20C	MT-ATP6	P00846	760
FAM20C	MT-ND4L	P03901	721
FAM20C	RPS3	P23396	720
FAM20C	MT-ND3	P03897	716
FAM20C	MT-ATP8	P03928	715
FAM20C	GASK1A	Q9UFP1	709
FAM20C	MT-ND2	P03891	696
FAM20C	MT-ND6	P03923	696
FAM20C	PHEX	P78562	686
FAM20C	PKDCC	Q504Y2	677
FAM20C	PTGS1	P23219	676

IntAct

103 interactions, top by confidence:

A	B	Type	Score
SPP1	FAM20C	psi-mi:“MI:0217”(phosphorylation reaction)	0.640
FAM20C	SPP1	psi-mi:“MI:0403”(colocalization)	0.640
SPP1	FAM20C	psi-mi:“MI:0915”(physical association)	0.640
FAM20C	SPP1	psi-mi:“MI:0217”(phosphorylation reaction)	0.620
FAM20C	CSN2	psi-mi:“MI:0217”(phosphorylation reaction)	0.620
FGA	FAM20C	psi-mi:“MI:0217”(phosphorylation reaction)	0.620
FAM20C	FGA	psi-mi:“MI:0217”(phosphorylation reaction)	0.620
FAM20C	FAM20A	psi-mi:“MI:0407”(direct interaction)	0.610
FAM20A	FAM20C	psi-mi:“MI:0915”(physical association)	0.610
	FAM20C	psi-mi:“MI:0882”(atpase reaction)	0.560
	FAM20C	psi-mi:“MI:0407”(direct interaction)	0.560
FAM20C	ENAM	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
FAM20C	AMTN	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
FAM20C	AMELX	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
ENAM	FAM20C	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
AMTN	FAM20C	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
FAM20C	AMBN	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
AMBN	FAM20C	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
FAM20C	CSN2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
FAM20C	APC	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
FAM20C	GTF2A1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
FAM20C	NHERF1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
FAM20C	IRF3	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
FAM20C	RELA	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
FAM20C		psi-mi:“MI:0217”(phosphorylation reaction)	0.440
FAM20C	FOS	psi-mi:“MI:0217”(phosphorylation reaction)	0.440

BioGRID (195): FAM20C (Affinity Capture-RNA), FAM20C (Affinity Capture-MS), FAM20C (Affinity Capture-MS), FAM20C (Synthetic Lethality), FAM20C (Affinity Capture-MS), FAM20C (Affinity Capture-MS), FAM20C (Proximity Label-MS), P4HB (Affinity Capture-MS), P4HA2 (Affinity Capture-MS), P4HA1 (Affinity Capture-MS), EDEM2 (Affinity Capture-MS), TRIM68 (Affinity Capture-MS), FKBP9 (Affinity Capture-MS), RCN1 (Affinity Capture-MS), SIL1 (Affinity Capture-MS)

ESM2 similar proteins: A0PJZ3, A2XFP3, A2XFT5, A2XFT6, B8AIZ4, C7J0P3, O04536, O48684, O88829, P08037, P15291, P15535, Q02527, Q09327, Q0V7R1, Q0WV13, Q10470, Q10MK2, Q10MQ0, Q16842, Q3UHH8, Q4G148, Q5CAZ6, Q5K027, Q5MJS3, Q5SP46, Q5ZKI6, Q68G12, Q6DE37, Q6GX83, Q6H765, Q6KB58, Q701R2, Q70D51, Q810K9, Q8CID3, Q8GWT1, Q8IXL6, Q8RXE1, Q92184

Diamond homologs: A4VCL2, O75063, Q5MJS3, Q5RH51, Q8CID3, Q8IXL6, Q8VCS3, Q95T10, Q96MK3, Q9XTW2

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
FAM20C	“down-regulates activity”	FGF23	phosphorylation
FAM20C	“up-regulates activity”	ERO1A	phosphorylation
FAM20C	“up-regulates activity”	PCSK9	phosphorylation
FAM20C	“down-regulates quantity”	SPP1	phosphorylation
FAM20C	“up-regulates activity”	STIM1	phosphorylation
FAM20C	“up-regulates activity”	SDF4	phosphorylation
FAM20C	“up-regulates activity”	VWF	phosphorylation
FAM20C	“up-regulates activity”	AMBN	phosphorylation
FAM20C	“up-regulates quantity”	DMP1	phosphorylation
FAM20C	“up-regulates activity”	SLC35G1	phosphorylation
FAM20C	“up-regulates activity”	HRC	phosphorylation
FAM20C	“up-regulates activity”	P4HB	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 81 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Post-translational protein phosphorylation	40	61.6×	9e-64
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	40	53.2×	5e-61
Response to elevated platelet cytosolic Ca2+	6	15.1×	2e-04
Platelet degranulation	10	13.5×	3e-07
ECM proteoglycans	5	11.6×	3e-03
Platelet activation, signaling and aggregation	6	9.8×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
biomineral tissue development	8	70.1×	1e-10
osteoblast differentiation	6	9.8×	5e-03
cell adhesion	10	5.1×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

598 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	8
Uncertain significance	197
Likely benign	239
Benign	92

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1023	NM_020223.4(FAM20C):c.1093G>C (p.Gly365Arg)	Pathogenic
1024	NM_020223.4(FAM20C):c.1163T>G (p.Leu388Arg)	Pathogenic
1026	NM_020223.4(FAM20C):c.957-3C>G	Pathogenic
1027	NM_020223.4(FAM20C):c.1136G>A (p.Gly379Glu)	Pathogenic
1028	NM_020223.4(FAM20C):c.1364-2A>G	Pathogenic
1029	NM_020223.4(FAM20C):c.956+5G>C	Pathogenic
1030	NM_020223.4(FAM20C):c.1446-1G>A	Pathogenic
1434418	NM_020223.4(FAM20C):c.708C>A (p.Tyr236Ter)	Pathogenic
149904	GRCh38/hg38 7p22.3(chr7:54165-725325)x1	Pathogenic
1676667	NM_020223.4(FAM20C):c.1094G>A (p.Gly365Asp)	Pathogenic
1676668	NG_033970.2:g.(8164_21328)_(21408_56449)del	Pathogenic
1910915	NM_020223.4(FAM20C):c.496G>T (p.Glu166Ter)	Pathogenic
2026111	NM_020223.4(FAM20C):c.1012A>T (p.Lys338Ter)	Pathogenic
2033175	NM_020223.4(FAM20C):c.127del (p.Glu43fs)	Pathogenic
2050437	NM_020223.4(FAM20C):c.162_163insCCGAA (p.Val55fs)	Pathogenic
2127258	NM_020223.4(FAM20C):c.1291C>T (p.Gln431Ter)	Pathogenic
2426528	NC_000007.13:g.(?193200)(208996_?)del	Pathogenic
2637599	NM_020223.4(FAM20C):c.474del (p.Ser159fs)	Pathogenic
3061677	NM_020223.4(FAM20C):c.1445G>A (p.Gly482Glu)	Pathogenic
30876	NM_020223.4(FAM20C):c.737T>A (p.Ile246Asn)	Pathogenic
30878	NM_020223.4(FAM20C):c.982C>T (p.Pro328Ser)	Pathogenic
4538529	NM_020223.4(FAM20C):c.307_308dup (p.Ser104fs)	Pathogenic
183311	NM_020223.4(FAM20C):c.1225C>T (p.Arg409Cys)	Likely pathogenic
2635570	NM_020223.4(FAM20C):c.1007T>G (p.Met336Arg)	Likely pathogenic
3034036	NM_020223.4(FAM20C):c.453_456del (p.Pro152fs)	Likely pathogenic
3068037	NM_020223.4(FAM20C):c.1331T>G (p.Val444Gly)	Likely pathogenic
30875	NM_020223.4(FAM20C):c.1351G>A (p.Asp451Asn)	Likely pathogenic
3391420	NM_020223.4(FAM20C):c.925_926insGGTG (p.Asn309delinsArgTer)	Likely pathogenic
4278334	NM_020223.4(FAM20C):c.1276T>C (p.Cys426Arg)	Likely pathogenic
4538528	GRCh37/hg19 7p22.3(chr7:170366-229852)x1	Likely pathogenic

SpliceAI

2606 predictions. Top by Δscore:

Variant	Effect	Δscore
7:193800:GACTG:G	donor_gain	1.0000
7:193805:G:T	donor_loss	1.0000
7:193806:T:G	donor_loss	1.0000
7:195526:T:A	acceptor_gain	1.0000
7:195729:GTGG:G	donor_gain	1.0000
7:195731:GG:G	donor_gain	1.0000
7:195732:GG:G	donor_gain	1.0000
7:195732:GGTA:G	donor_loss	1.0000
7:195733:G:GA	donor_loss	1.0000
7:195733:G:GG	donor_gain	1.0000
7:195734:T:A	donor_loss	1.0000
7:208977:G:GG	donor_gain	1.0000
7:246413:A:AG	acceptor_gain	1.0000
7:246414:G:GG	acceptor_gain	1.0000
7:255847:A:AG	acceptor_gain	1.0000
7:255848:G:GT	acceptor_gain	1.0000
7:255848:GCC:G	acceptor_gain	1.0000
7:255848:GCCA:G	acceptor_gain	1.0000
7:255976:G:GT	donor_gain	1.0000
7:256025:GCCGA:G	donor_gain	1.0000
7:256028:GA:G	donor_gain	1.0000
7:256030:GTGA:G	donor_gain	1.0000
7:256649:CGCAG:C	acceptor_loss	1.0000
7:256652:A:AG	acceptor_gain	1.0000
7:256652:A:T	acceptor_loss	1.0000
7:256652:AGGT:A	acceptor_gain	1.0000
7:256652:AGGTG:A	acceptor_gain	1.0000
7:256653:G:GG	acceptor_gain	1.0000
7:256653:GGT:G	acceptor_gain	1.0000
7:256653:GGTG:G	acceptor_gain	1.0000

AlphaMissense

3809 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:208926:G:C	K271N	1.000
7:208926:G:T	K271N	1.000
7:208928:T:C	L272P	1.000
7:208966:A:G	K285E	1.000
7:208968:A:C	K285N	1.000
7:208968:A:T	K285N	1.000
7:246455:T:C	F302L	1.000
7:246456:T:C	F302S	1.000
7:246456:T:G	F302C	1.000
7:246457:C:A	F302L	1.000
7:246457:C:G	F302L	1.000
7:246468:A:T	E306V	1.000
7:246471:G:C	R307T	1.000
7:246471:G:T	R307M	1.000
7:246472:G:C	R307S	1.000
7:246472:G:T	R307S	1.000
7:255860:T:A	C362S	1.000
7:255860:T:C	C362R	1.000
7:255861:G:A	C362Y	1.000
7:255861:G:C	C362S	1.000
7:255861:G:T	C362F	1.000
7:255862:C:G	C362W	1.000
7:255870:G:A	G365D	1.000
7:255875:T:A	C367S	1.000
7:255875:T:C	C367R	1.000
7:255876:G:A	C367Y	1.000
7:255876:G:C	C367S	1.000
7:255876:G:T	C367F	1.000
7:255877:T:G	C367W	1.000
7:255887:T:A	C371S	1.000

dbSNP variants (sampled 300 via entrez): RS1000052901 (7:201445 G>T), RS1000110256 (7:241477 G>C), RS1000110675 (7:210672 G>A), RS1000127689 (7:231723 C>G,T), RS1000140948 (7:247315 G>A,T), RS1000153196 (7:206273 C>A,G), RS1000161691 (7:218542 G>A), RS1000179288 (7:202862 T>C), RS1000190387 (7:230379 G>A,C,T), RS1000249426 (7:235112 C>T), RS1000279745 (7:206494 C>G), RS1000294160 (7:210478 C>G,T), RS1000302991 (7:210582 C>T), RS1000334541 (7:227973 C>T), RS1000341478 (7:245805 C>T)

Disease associations

OMIM: gene MIM:611061 | disease phenotypes: MIM:259660, MIM:259775

GenCC curated gene-disease

Disease	Classification	Inheritance
lethal osteosclerotic bone dysplasia	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
lethal osteosclerotic bone dysplasia	Definitive	AR

Mondo (2): lethal osteosclerotic bone dysplasia (MONDO:0009821), cerebral cortical dysplasia (MONDO:0017094)

Orphanet (2): Osteosclerotic bone dysplasia (Orphanet:1832), Cerebral cortical dysplasia (Orphanet:268950)

HPO phenotypes

65 total (30 of 65 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000072	Hydroureter
HP:0000126	Hydronephrosis
HP:0000154	Wide mouth
HP:0000160	Narrow mouth
HP:0000169	Gingival fibromatosis
HP:0000175	Cleft palate
HP:0000212	Gingival overgrowth
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000239	Large fontanelles
HP:0000244	Brachyturricephaly
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000270	Delayed cranial suture closure
HP:0000272	Malar flattening
HP:0000278	Retrognathia
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000410	Mixed hearing impairment
HP:0000411	Protruding ear
HP:0000452	Choanal stenosis
HP:0000453	Choanal atresia
HP:0000457	Depressed nasal ridge
HP:0000463	Anteverted nares
HP:0000470	Short neck

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002550_7	Allergic rhinitis	1.000000e-07
GCST002817_8	Alzheimer’s disease in APOE e4- carriers	2.000000e-06

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D054220	Malformations of Cortical Development	C10.500.507; C16.131.666.507
C535282	Raine syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4879492 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.21	IC50	6243	nM	CHEMBL4847900

PubChem BioAssay actives

1 with measured affinity, of 24 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methoxy-N-[4-[[4-(3,4,5-trimethoxyanilino)pyrimidin-2-yl]amino]phenyl]benzenesulfonamide	1755933: Inhibition of Fam20C (unknown origin) assessed as reduction in inorganic phosphate release in presence of ATP measured by Malachite green phosphate staining based micro plate reader assay	ic50	6.2430	uM

CTD chemical–gene interactions

56 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases methylation	7
Benzo(a)pyrene	decreases expression, decreases methylation	4
sodium arsenite	affects expression, decreases expression, increases expression	3
Aflatoxin B1	decreases expression, increases methylation	3
entinostat	affects cotreatment, increases expression	2
Cisplatin	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Smoke	decreases expression, increases expression	2
Tobacco Smoke Pollution	increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, decreases expression	1
bisphenol A	decreases methylation	1
lead acetate	increases expression	1
trichostatin A	decreases expression	1
methylparaben	increases expression	1
afimoxifene	decreases expression, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
benzo(e)pyrene	increases methylation	1
ferrous chloride	decreases expression	1
cupric chloride	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression, affects response to substance, increases expression, affects cotreatment	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
abrine	decreases expression	1
dorsomorphin	increases expression, decreases expression, affects cotreatment	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	decreases expression	1
jinfukang	increases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	decreases expression	1
Vorinostat	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4814755	Binding	Inhibition of Fam20C (unknown origin) assessed as reduction in inorganic phosphate release in presence of ATP at 10 uM measured by Malachite green phosphate staining based micro plate reader assay relative to control	Discovery of a novel small-molecule inhibitor of Fam20C that induces apoptosis and inhibits migration in triple negative breast cancer. — Eur J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E1WS	HAP1 FAM20C (-) 1	Cancer cell line	Male
CVCL_E1WT	HAP1 FAM20C (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

3 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02261753	Not specified	TERMINATED	Evaluating Dietary Intervention Before surgicaL Treatment for Epilepsy
NCT02654340	Not specified	TERMINATED	Biomarkers for Tuberous Sclerosis Complex (BioTuScCom)
NCT06915649	Not specified	RECRUITING	Exploration and Evaluation of Amygdalo-Hippocampectomy According to Prof. Coubes’ Technique: An Anatomical, Clinical, and Educational Approach