GCM2

Summary

GCM2 (GCM transcription factor 2, HGNC:4198) is a protein-coding gene on chromosome 6p24.2, encoding Chorion-specific transcription factor GCMb (O75603). Transcription factor that binds specific sequences on gene promoters and activate their transcription.

This gene is a homolog of the Drosophila glial cells missing gene, which is thought to act as a binary switch between neuronal and glial cell determination. The protein encoded by this gene contains a conserved N-terminal GCM motif that has DNA-binding activity. The protein is a transcription factor that acts as a master regulator of parathyroid development. It has been suggested that this transcription factor might mediate the effect of calcium on parathyroid hormone expression and secretion in parathyroid cells. Mutations in this gene are associated with hypoparathyroidism.

Source: NCBI Gene 9247 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypoparathyroidism, familial isolated, 2 (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 302 total — 14 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 26
• MANE Select transcript: NM_004752

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4198
Approved symbol	GCM2
Name	GCM transcription factor 2
Location	6p24.2
Locus type	gene with protein product
Status	Approved
Aliases	hGCMb
Ensembl gene	ENSG00000124827
Ensembl biotype	protein_coding
OMIM	603716
Entrez	9247

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000379491

RefSeq mRNA: 1 — MANE Select: NM_004752 NM_004752

CCDS: CCDS4517

Canonical transcript exons

ENST00000379491 — 5 exons

Exon	Start	End
ENSE00000684768	10876445	10876557
ENSE00000684770	10877140	10877392
ENSE00000848008	10875891	10876016
ENSE00001481271	10873223	10874933
ENSE00001481289	10881704	10882041

Expression profiles

Bgee: expression breadth tissue_specific, 9 present calls, max score 80.22.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0171 / max 17.1381, expressed in 4 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
71701	0.0171	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.22	gold quality
pancreatic ductal cell	CL:0002079	55.97	silver quality
ileal mucosa	UBERON:0000331	52.17	silver quality
epithelial cell of pancreas	CL:0000083	50.50	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
quadriceps femoris	UBERON:0001377	49.04	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
deltoid	UBERON:0001476	48.82	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
vastus lateralis	UBERON:0001379	48.25	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
upper arm skin	UBERON:0004263	48.06	gold quality
cervix epithelium	UBERON:0004801	48.04	gold quality
oviduct epithelium	UBERON:0004804	48.00	gold quality
tongue squamous epithelium	UBERON:0006919	47.92	gold quality
mucosa of urinary bladder	UBERON:0001259	47.80	gold quality
metanephric glomerulus	UBERON:0004736	47.45	gold quality
thymus	UBERON:0002370	47.42	gold quality
kidney epithelium	UBERON:0004819	47.39	gold quality
nephron tubule	UBERON:0001231	47.30	gold quality
diaphragm	UBERON:0001103	47.05	gold quality
gluteal muscle	UBERON:0002000	47.03	gold quality
triceps brachii	UBERON:0001509	47.01	gold quality
bone marrow cell	CL:0002092	46.18	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.46

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
CASR	Activation
PTH	Activation

JASPAR motifs

Motif	Name	Family
MA0767.1	GCM2	GCM
MA0767.2	GCM2	GCM

JASPAR matrix evidence (PMIDs): PMID:8962155

Upstream regulators (CollecTRI, top): GATA3

miRNA regulators (miRDB)

36 targeting GCM2, 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-150-5P	99.99	66.69	1976
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-8064	99.45	66.92	875
HSA-MIR-3140-5P	99.39	69.04	1136
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-548B-3P	99.38	67.26	1000
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-190B-3P	99.33	68.29	1382
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-3606-3P	99.11	69.84	3254
HSA-MIR-12135	98.99	70.26	1814
HSA-MIR-935	98.82	69.36	1072
HSA-MIR-3161	98.71	67.14	816
HSA-MIR-4317	98.49	67.09	987
HSA-MIR-2681-3P	98.18	65.28	577
HSA-MIR-6834-3P	98.16	65.77	551
HSA-MIR-6529-5P	97.85	66.47	673
HSA-MIR-6747-3P	97.73	64.84	1596

Literature-anchored findings (GeneRIF, showing 27)

• The glial cell missing gene, GCMB , encodes a transcription factor, which is a master regulator of parathyroid development. GCMB expression is upregulated in abnormal parathyroid glands of hyperparathyroidism and decreases in response to hypocalcemia. (PMID:15657585)
• Although GCM2 mutations appear to be an uncommon cause of isolated hypoparathyroidism, the wide variety of GCM2 polymorphisms suggests that variant alleles may have a role in determining parathyroid function. (PMID:18182452)
• The dominant-negative effect observed in vitro for both GCMB mutations provides a plausible explanation for the impaired PTH secretion observed in the two unrelated families with autosomal dominant form of hypoparathyroidism. (PMID:18583467)
• Glial cells missing-2 (GCM2) transactivates the calcium-sensing receptor gene (PMID:18712808)
• one function of Gcm2 is to maintain high levels of CaR expression in parathyroid cells. (PMID:19257819)
• significant association of R110W variant of GCM2 with isolated hypoparathyroidism (PMID:19940031)
• These results expand the spectrum of hypoparathyroidism-associated GCMB mutations and help elucidate the molecular mechanisms underlying DNA-binding and transactivation that are required for this parathyroid-specific transcription factor. (PMID:20190276)
• Our results have identified the first dominant missense GCMB mutation and help to increase our understanding of the mechanism underlying gene transactivation that is a prerequisite for the function of this parathyroid gland-specific transcription factor. (PMID:20463099)
• These results indicate that GCMB and vitamin D receptor are involved in the positive and negative regulation of parathyroid hormone gene expression, respectively. (PMID:20558332)
• Gcm2 is a useful adjunct marker for the diagnosis of parathyroid lesions. (PMID:21164298)
• We conclude that mutations in the transcription factor GCMB do not seem to play a major role in the pathogenesis of primary hyperparathyroidism. (PMID:21642377)
• Data suggest that replacement of cysteine 106 with arginine (C106R) would interfere with DNA binding of glial cells missing B (GCMB). (PMID:22066718)
• First described GCM2 mutation in exon 3 in patients with severe congenital hypoparathyroidism. (PMID:23155703)
• Four single nucleotide polymorphisms of GCMB gene were found in the GCMB gene (c.-44T > C [rs16870746], c.91-242A > G [rs9379881], c.343+163G > A [rs9393726], and c.583-72A > T [rs2076257]) in our cohort. (PMID:24133354)
• we identified the genetic defect in 35% of hypoparathyroidism patients in our cohort and discovered novel GCM2 mutations including submicroscopic deletion that was undetectable by array comparative genomic hybridization (PMID:25137426)
• The higher frequency of GCM2 282D in primary hyperparathyroidismand enhanced transcriptional activity of this variant supports the notion that it could contribute causally to parathyroid tumorigenesis (PMID:25279501)
• Gata3 interacted with Gcm2 and MafB, two known transcriptional regulators of parathyroid development, and synergistically stimulated the PTH promoter. (PMID:25917456)
• Our results demonstrate that germline-activating mutations affecting the C-terminal conserved inhibitory domain of GCM2 can cause familial isolated hyperparathyroidism. (PMID:27745835)
• The present study investigated the prevalence of the Y282D variant of the GCM2 gene and its association with clinical parameters in patients with a definitive histological diagnosis of sporadic parathyroid carcinoma (SPC) or atypical adenoma (AA). (PMID:28609842)
• GCM2-associated primary hyperparathyroidism patients have greater preoperative parathyroid hormone levels, a greater rate of multigland disease, a lesser rate of biochemical cure (PMID:29108698)
• Activating GCM2 C-terminal conserved inhibitory domain (CCID) variants (p.V382M and p.Y394S) were identified in six of 396 adenomas (1.52%), and a hyperparathyroidism-associated GCM2 non-CCID activating variant (p.Y282D) was found in 20 adenomas (5.05%). The overall frequency of tested activating GCM2 variants in this study was 6.57%, approximately threefold greater than their frequency in the general population. (PMID:30624640)
• Germline GCM2 Mutation Screening in Chinese Primary Hyperparathyroidism Patients. (PMID:33471711)
• Five patients with disorders of calcium metabolism presented with GCM2 gene variants. (PMID:33536578)
• GCM2 Silencing in Parathyroid Adenoma Is Associated With Promoter Hypermethylation and Gain of Methylation on Histone 3. (PMID:34077544)
• GCM2 Variants in Familial and Multiglandular Primary Hyperparathyroidism. (PMID:34967908)
• Novel Glial Cells Missing-2 (GCM2) variants in parathyroid disorders. (PMID:35038313)
• GCM2 p.Tyr394Ser variant in Ashkenazi Israeli patients with suspected familial isolated hyperparathyroidism. (PMID:38130397)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gcm2	ENSDARG00000045413
mus_musculus	Gcm2	ENSMUSG00000021362
rattus_norvegicus	Gcm2	ENSRNOG00000015008
drosophila_melanogaster	gcm	FBGN0014179
drosophila_melanogaster	gcm2	FBGN0019809

Paralogs (1): GCM1 (ENSG00000137270)

Protein

Protein identifiers

Chorion-specific transcription factor GCMb — O75603 (reviewed: O75603)

Alternative names: GCM motif protein 2, Glial cells missing homolog 2

All UniProt accessions (1): O75603

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that binds specific sequences on gene promoters and activate their transcription. Through the regulation of gene transcription, may play a role in parathyroid gland development.

Subcellular location. Nucleus.

Disease relevance. Hypoparathyroidism, familial isolated, 2 (FIH2) [MIM:618883] An autosomal recessive form of hypoparathyroidism, a disorder characterized by hypocalcemia and hyperphosphatemia due to a deficiency of parathyroid hormone. Clinical features include seizures, tetany and cramps. The disease is caused by variants affecting the gene represented in this entry. Hyperparathyroidism 4 (HRPT4) [MIM:617343] A form of familial primary hyperparathyroidism, a hypercalcemic disorder caused by inappropriate oversecretion of parathyroid hormone due to parathyroid hyperplasia or neoplasms. Clinical features include hypercalcemia, phosphaturia, and increased bone resorption. HRPT4 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The C-terminal conserved inhibitory domain (CCID) negatively regulates the transcriptional activity of the protein.

RefSeq proteins (1): NP_004743* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003902	Tscrpt_reg_GCM	Domain
IPR036115	GCM_dom_sf	Homologous_superfamily
IPR039791	GCM	Family
IPR043020	GCM_large	Homologous_superfamily
IPR043021	GCM_small	Homologous_superfamily

Pfam: PF03615

UniProt features (28 total): sequence variant 15, binding site 8, region of interest 2, chain 1, DNA-binding region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75603-F1	58.78	0.28

Functional residue map

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

Ligand- & substrate-binding residues (8): 130; 157; 159; 81; 87; 91; 118; 121

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 125 (showing top): BENPORATH_ES_WITH_H3K27ME3, chr6p24, GOBP_NEUROGENESIS, GOBP_MONOATOMIC_ION_HOMEOSTASIS, GOBP_ENDOCRINE_SYSTEM_DEVELOPMENT, MODULE_48, MODULE_95, RIZ_ERYTHROID_DIFFERENTIATION, GOBP_HOMEOSTATIC_PROCESS, GOBP_CHEMICAL_HOMEOSTASIS, MODULE_220, RIZ_ERYTHROID_DIFFERENTIATION_6HR, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, GOBP_GLAND_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_TRANSCRIPTION_BY_RNA_POLYMERASE_II

GO Biological Process (8): regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), intracellular calcium ion homeostasis (GO:0006874), intracellular phosphate ion homeostasis (GO:0030643), gliogenesis (GO:0042063), parathyroid gland development (GO:0060017), regulation of DNA-templated transcription (GO:0006355), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (8): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
transcription by RNA polymerase II	2
DNA-templated transcription	2
regulation of transcription by RNA polymerase II	2
regulation of DNA-templated transcription	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
phosphate ion homeostasis	1
intracellular chemical homeostasis	1
neurogenesis	1
endocrine system development	1
gland development	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
DNA binding	1
cation binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

706 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GCM2	CASR	P41180	943
GCM2	PTH	P01270	884
GCM2	FOXN1	O15353	710
GCM2	GNA11	P29992	663
GCM2	CDC73	Q6P1J9	659
GCM2	AP2S1	P53680	615
GCM2	MAFB	Q9Y5Q3	612
GCM2	FOXI3	A8MTJ6	606
GCM2	PAX1	P15863	588
GCM2	MEN1	O00255	574
GCM2	TBX1	O43435	572
GCM2	AIRE	O43918	519
GCM2	PAX9	P55771	471
GCM2	RET	P07949	455
GCM2	TRPV5	Q9NQA5	450

IntAct

139 interactions, top by confidence:

A	B	Type	Score
CRX	GCM2	psi-mi:“MI:0915”(physical association)	0.890
GCM2	FHL3	psi-mi:“MI:0915”(physical association)	0.890
GCM2	HSFY1	psi-mi:“MI:0915”(physical association)	0.890
FHL3	GCM2	psi-mi:“MI:0915”(physical association)	0.890
HSFY1	GCM2	psi-mi:“MI:0915”(physical association)	0.890
GCM2	CRX	psi-mi:“MI:0915”(physical association)	0.890
RBPMS	GCM2	psi-mi:“MI:0915”(physical association)	0.740

BioGRID (47): GCM2 (Two-hybrid), GCM2 (Two-hybrid), RBPMS (Two-hybrid), HSFY1 (Two-hybrid), GCM2 (Synthetic Lethality), CRX (Two-hybrid), FHL3 (Two-hybrid), HSFY1 (Two-hybrid), RBPMS (Two-hybrid), CSTF1 (Affinity Capture-MS), FHL3 (Two-hybrid), CRX (Two-hybrid), HSFY2 (Two-hybrid), RBPMS (Two-hybrid), GCM2 (Two-hybrid)

ESM2 similar proteins: A0A0D1DMJ6, A0A0F0I5G4, A0A0S6XAX9, A0A1L9WQN2, A0A1U9YI06, A0A2U8U2L8, A0A345BJN6, A0A7M4BDQ2, A2QA83, A4II20, B0Y9W4, B4XXY3, B6GVZ2, B7WN96, K0DZ91, K9GKQ6, N4XMB0, O75603, P10069, P20945, P40656, P48590, Q01196, Q03347, Q05159, Q08427, Q08775, Q09602, Q09824, Q12531, Q27403, Q2U9L6, Q2UQZ5, Q4WPF5, Q4WRE4, Q4WV91, Q58L83, Q5B7I8, Q5BBM1, Q5RFT9

Diamond homologs: O09102, O75603, P70348, Q27403, Q9NP62, Q9VLA2, Q9Z288

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
GCM2	“up-regulates quantity by expression”	CASR	“transcriptional regulation”
GCM2	“up-regulates quantity by expression”	PTH	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	12
Uncertain significance	172
Likely benign	51
Benign	33

Top pathogenic / likely-pathogenic (26)

Variant ID	HGVS	Classification
1065410	NM_004752.4(GCM2):c.1400del (p.Pro467fs)	Pathogenic
1065411	NM_004752.4(GCM2):c.1389del (p.His465fs)	Pathogenic
1456025	NC_000006.11:g.(?10876124)(10882026_?)del	Pathogenic
2417241	NM_004752.4(GCM2):c.1104C>A (p.Tyr368Ter)	Pathogenic
2425224	NC_000006.11:g.(?10876126)(10883962_?)del	Pathogenic
2691426	NM_004752.4(GCM2):c.22G>T (p.Glu8Ter)	Pathogenic
3246185	NC_000006.11:g.(?10876126)(10883916_?)del	Pathogenic
3769019	NC_000006.11:g.(10875167_10876123)(10882275?)del	Pathogenic
433163	NC_000006.12:g.(?10875891)(10881865_?)del	Pathogenic
433164	NM_004752.4(GCM2):c.408C>A (p.Tyr136Ter)	Pathogenic
433165	NM_004752.4(GCM2):c.456+2dup	Pathogenic
6090	NG_008970.1:g.3172_(10967_10971)del	Pathogenic
6091	NM_004752.4(GCM2):c.140G>T (p.Arg47Leu)	Pathogenic
64623	NM_004752.4(GCM2):c.893del (p.Ile298fs)	Pathogenic
1299514	NM_004752.4(GCM2):c.1A>G (p.Met1Val)	Likely pathogenic
1341348	NM_004752.4(GCM2):c.1148T>C (p.Ile383Thr)	Likely pathogenic
1917623	NM_004752.4(GCM2):c.90+2T>G	Likely pathogenic
2444139	NM_004752.4(GCM2):c.853del (p.Ser285fs)	Likely pathogenic
3041710	NM_004752.4(GCM2):c.199C>T (p.Arg67Cys)	Likely pathogenic
3068139	NM_004752.4(GCM2):c.199C>G (p.Arg67Gly)	Likely pathogenic
3359776	NM_004752.4(GCM2):c.115C>T (p.Arg39Ter)	Likely pathogenic
3391440	NM_004752.4(GCM2):c.1098C>A (p.Cys366Ter)	Likely pathogenic
3592949	NM_004752.4(GCM2):c.1216C>T (p.Arg406Ter)	Likely pathogenic
3592955	NM_004752.4(GCM2):c.1100_1103del (p.Arg367fs)	Likely pathogenic
3592958	NM_004752.4(GCM2):c.1048C>T (p.Gln350Ter)	Likely pathogenic
372876	NM_004752.4(GCM2):c.1504A>G (p.Asn502Asp)	Likely pathogenic

SpliceAI

847 predictions. Top by Δscore:

Variant	Effect	Δscore
6:10875882:C:CA	donor_gain	1.0000
6:10876017:C:CC	acceptor_gain	1.0000
6:10877120:C:CA	donor_gain	1.0000
6:10877133:T:TA	donor_gain	1.0000
6:10877138:A:AC	donor_gain	1.0000
6:10877139:C:CC	donor_gain	1.0000
6:10877139:CT:C	donor_gain	1.0000
6:10877139:CTCTG:C	donor_gain	1.0000
6:10877182:G:C	donor_gain	1.0000
6:10877248:T:TA	donor_gain	1.0000
6:10877388:AGCTC:A	acceptor_gain	1.0000
6:10877389:GCTC:G	acceptor_gain	1.0000
6:10877390:CTC:C	acceptor_gain	1.0000
6:10877390:CTCC:C	acceptor_gain	1.0000
6:10877391:TC:T	acceptor_gain	1.0000
6:10877391:TCCT:T	acceptor_gain	1.0000
6:10877392:CC:C	acceptor_gain	1.0000
6:10877393:C:CC	acceptor_gain	1.0000
6:10877393:C:CG	acceptor_loss	1.0000
6:10877394:T:G	acceptor_loss	1.0000
6:10881700:TTA:T	donor_loss	1.0000
6:10881701:TACC:T	donor_loss	1.0000
6:10881702:A:AC	donor_gain	1.0000
6:10881702:AC:A	donor_gain	1.0000
6:10881703:C:A	donor_loss	1.0000
6:10881703:C:CG	donor_gain	1.0000
6:10881703:CC:C	donor_gain	1.0000
6:10876014:GGCCT:G	acceptor_loss	0.9900
6:10877401:G:C	acceptor_gain	0.9900
6:10877401:G:GC	acceptor_gain	0.9900

AlphaMissense

3345 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:10877246:C:A	K79N	1.000
6:10877246:C:G	K79N	1.000
6:10877248:T:C	K79E	1.000
6:10877249:C:A	K78N	1.000
6:10877249:C:G	K78N	1.000
6:10877291:C:A	W64C	1.000
6:10877291:C:G	W64C	1.000
6:10877293:A:G	W64R	1.000
6:10877293:A:T	W64R	1.000
6:10876475:C:A	W142C	0.999
6:10876475:C:G	W142C	0.999
6:10876477:A:G	W142R	0.999
6:10876477:A:T	W142R	0.999
6:10876478:A:C	F141L	0.999
6:10876478:A:T	F141L	0.999
6:10876479:A:G	F141S	0.999
6:10876480:A:G	F141L	0.999
6:10876481:G:C	N140K	0.999
6:10876481:G:T	N140K	0.999
6:10876511:A:C	C130W	0.999
6:10876513:A:G	C130R	0.999
6:10877165:G:C	C106W	0.999
6:10877166:C:T	C106Y	0.999
6:10877167:A:G	C106R	0.999
6:10877169:A:T	I105N	0.999
6:10877172:G:T	A104D	0.999
6:10877222:A:C	C87W	0.999
6:10877224:A:G	C87R	0.999
6:10877236:C:G	G83R	0.999
6:10877240:G:C	C81W	0.999

dbSNP variants (sampled 300 via entrez): RS1000245570 (6:10882893 G>T), RS1000322739 (6:10883438 CA>C,CAA), RS1000323614 (6:10877791 A>G), RS1000458716 (6:10883900 C>G), RS1000524144 (6:10882700 T>G), RS1001106097 (6:10876386 T>C), RS1001208271 (6:10877103 C>G), RS1001428933 (6:10877813 A>G), RS1001616765 (6:10876901 T>A,C), RS1001649134 (6:10883631 G>C), RS1001986277 (6:10882199 A>C,G), RS1002394076 (6:10878718 A>G), RS1002426994 (6:10872850 A>G), RS1002458208 (6:10873103 T>C,G), RS1002688900 (6:10874007 ATT>A)

Disease associations

OMIM: gene MIM:603716 | disease phenotypes: MIM:618883, MIM:617343, MIM:146200

GenCC curated gene-disease

Disease	Classification	Inheritance
hyperparathyroidism 4	Strong	Autosomal dominant
hypoparathyroidism, familial isolated, 2	Strong	Autosomal recessive
familial isolated hypoparathyroidism due to agenesis of parathyroid gland	Supportive	Autosomal recessive
familial isolated hyperparathyroidism	Supportive	Autosomal dominant

Mondo (5): hypoparathyroidism, familial isolated, 2 (MONDO:0020798), hyperparathyroidism 4 (MONDO:0024570), familial hypoparathyroidism (MONDO:0016390), familial isolated hypoparathyroidism due to agenesis of parathyroid gland (MONDO:0010618), familial isolated hyperparathyroidism (MONDO:0015027)

Orphanet (1): Familial isolated hypoparathyroidism (Orphanet:2238)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000121	Nephrocalcinosis
HP:0000787	Nephrolithiasis
HP:0000934	Chondrocalcinosis
HP:0000938	Osteopenia
HP:0002148	Hypophosphatemia
HP:0002150	Hypercalciuria
HP:0002199	Hypocalcemic seizures
HP:0002897	Parathyroid adenoma
HP:0002901	Hypocalcemia
HP:0002905	Hyperphosphatemia
HP:0002917	Hypomagnesemia
HP:0003072	Hypercalcemia
HP:0003109	Hyperphosphaturia
HP:0003165	Elevated circulating parathyroid hormone level
HP:0003251	Male infertility
HP:0003581	Adult onset
HP:0006780	Parathyroid carcinoma
HP:0008198	Congenital hypoparathyroidism
HP:0008200	Primary hyperparathyroidism
HP:0008211	Parathyroid agenesis
HP:0011458	Abdominal symptom
HP:0031817	Decreased circulating parathyroid hormone level
HP:0040160	Generalized osteoporosis

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000403_2	Menarche and menopause (age at onset)	5.000000e-08
GCST009172_2	Response to (pegylated) interferon in HBeAg-negative hepatitis B	3.000000e-06
GCST009391_1579	Metabolite levels	4.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0007859	response to interferon
EFO:0010349	cholesteryl ester 20:5 measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C537156	Hypoparathyroidism familial isolated (supp.)
C563238	Parathyroid Glands, Agenesis Of (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

7 total (human), top 7 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression	2
2-methyl-4-isothiazolin-3-one	increases expression	1
trichostatin A	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Sirolimus	affects activity, increases reaction	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01369953	Not specified	COMPLETED	Informed Consent for Whole Genome Sequencing: Ideals and Norms Referenced by Early Participants