FKBP14

Summary

FKBP14 (FKBP prolyl isomerase 14, HGNC:18625) is a protein-coding gene on chromosome 7p14.3, encoding Peptidyl-prolyl cis-trans isomerase FKBP14 (Q9NWM8). PPIase which accelerates the folding of proteins during protein synthesis.

The protein encoded by this gene is a member of the FK506-binding protein family of peptidyl-prolyl cis-trans isomerases. The encoded protein is found in the lumen of the endoplasmic reticulum, where it is thought to accelerate protein folding. Defects in this gene are a cause of a type of Ehlers-Danlos syndrome (EDS). Both a protein-coding variant and noncoding variants are transcribed from this gene.

Source: NCBI Gene 55033 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Ehlers-Danlos syndrome, kyphoscoliotic type, 2 (Definitive, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 214 total — 9 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 55
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_017946

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18625
Approved symbol	FKBP14
Name	FKBP prolyl isomerase 14
Location	7p14.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20731, FKBP22
Ensembl gene	ENSG00000106080
Ensembl biotype	protein_coding
OMIM	614505
Entrez	55033

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 nonsense_mediated_decay, 1 protein_coding, 1 retained_intron

ENST00000222803, ENST00000412494, ENST00000419018, ENST00000479939

RefSeq mRNA: 1 — MANE Select: NM_017946 NM_017946

CCDS: CCDS5423

Canonical transcript exons

ENST00000222803 — 4 exons

Exon	Start	End
ENSE00000674693	30022665	30022816
ENSE00001138174	30010587	30014893
ENSE00001138183	30026312	30026702
ENSE00003659198	30018996	30019123

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 95.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.4549 / max 221.5980, expressed in 1705 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
83421	12.4549	1705

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	95.32	gold quality
corpus epididymis	UBERON:0004359	91.28	gold quality
cartilage tissue	UBERON:0002418	89.77	gold quality
stromal cell of endometrium	CL:0002255	88.78	gold quality
smooth muscle tissue	UBERON:0001135	88.48	gold quality
cauda epididymis	UBERON:0004360	86.59	gold quality
heart right ventricle	UBERON:0002080	86.48	gold quality
skin of hip	UBERON:0001554	85.49	gold quality
upper leg skin	UBERON:0004262	84.80	gold quality
islet of Langerhans	UBERON:0000006	84.70	gold quality
seminal vesicle	UBERON:0000998	84.70	gold quality
calcaneal tendon	UBERON:0003701	84.26	gold quality
caput epididymis	UBERON:0004358	83.58	gold quality
parietal pleura	UBERON:0002400	83.47	gold quality
rectum	UBERON:0001052	82.78	gold quality
endometrium	UBERON:0001295	82.67	gold quality
body of pancreas	UBERON:0001150	82.37	gold quality
pancreas	UBERON:0001264	82.16	gold quality
pleura	UBERON:0000977	81.96	gold quality
tendon	UBERON:0000043	81.93	gold quality
decidua	UBERON:0002450	81.80	gold quality
adrenal tissue	UBERON:0018303	81.67	gold quality
visceral pleura	UBERON:0002401	81.60	gold quality
periodontal ligament	UBERON:0008266	81.52	gold quality
ventricular zone	UBERON:0003053	81.41	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.39	gold quality
parotid gland	UBERON:0001831	81.08	silver quality
colonic epithelium	UBERON:0000397	80.98	gold quality
adenohypophysis	UBERON:0002196	80.42	gold quality
pituitary gland	UBERON:0000007	80.31	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.40

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

134 targeting FKBP14, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 15)

• study demonstrated FKBP14 is localized in the endoplasmic reticulum (ER) and that deficiency of FKBP14 leads to enlarged ER cisterns in dermal fibroblasts in vivo. (PMID:22265013)
• A 1.9 A resolution crystal structure for human FKBP22 has been determined. The EF-hand motifs of two FKBP22 molecules form a dimeric complex with an elongated and predominantly hydrophobic cavity that can potentially be occupied by an aliphatic ligand. (PMID:24272907)
• the occurrence of umbilical skin redundancy in association with two other syndromes: Morquio syndrome and FKBP14-related Ehlers-Danlos syndrome (EDS), is reported. (PMID:24773188)
• FKBP22 catalyzes the folding of type III collagen and only interacts with type III type VI and type X collagen. (PMID:24821723)
• FKBP14 expression was elevated in ovarian cancer tissues when compared with matched normal tissues. Lentiviral shRNA mediated knockdown of FKBP14 and suppressed the growth of ovarian cancer cells via arresting the cell cycle in the G0/G1 phase and stimulating cell apoptosis. Moreover, cell apoptosis induced by FKBP14 RNAi was mediated by enhancing the ratio of Bax/Bcl-2. (PMID:27131312)
• this report describes a potentially life-threatening vascular complication in early pediatric age and atlantoaxial instability, suggesting the need for FKBP14-related EDS patients of tailored follow-up that includes cardiovascular monitoring, that is, cerebral, thoracic and abdominal MRA, and cervical dynamic radiograph. (PMID:27149304)
• Genetic studies showed that the patient harboured a homozygous mutation (c.362dupC p.Glu122Argfs*7) in the FKBP14 gene, confirming kyphoscoliotic EDS related to this gene. (PMID:27905128)
• observed changes in activity of six rER-resident PPIases, cyclophilin B (encoded by the PPIB gene), FKBP13 (FKBP2), FKBP19 (FKBP11), FKBP22 (FKBP14), FKBP23 (FKBP7), and FKBP65 (FKBP10), due to posttranslational modifications of proline residues in the substrate. (PMID:28385890)
• FKBP14 may act as an oncogene through suppressing apoptosis and promoting motility in human cervical carcinogenesis. (PMID:28731139)
• This patient points out the existence of a wider phenotypic spectrum of FKBP14-kEDS to include early onset muscle disease. (PMID:30561154)
• The novel missense mutation Met48Lys in FKBP22 changes its structure and functions. (PMID:31949249)
• A floppy infant without lingual frenulum and kyphoscoliosis: Ehlers Danlos syndrome case report. (PMID:33579342)
• Ehlers-Danlos syndrome kyphoscoliotic type 2 caused by mutations in the FKBP14 gene: an analysis of five cases. (PMID:34504686)
• Kyphoscoliotic Ehlers-Danlos syndrome caused by pathogenic variants in FKBP14: Further insights into the phenotypic spectrum and pathogenic mechanisms. (PMID:36054293)
• Local Net Charge State of Collagen Triple Helix Is a Determinant of FKBP22 Binding to Collagen III. (PMID:37894834)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	fkbp14	ENSDARG00000040695
mus_musculus	Fkbp14	ENSMUSG00000038074
rattus_norvegicus	Fkbp14	ENSRNOG00000009886
caenorhabditis_elegans		WBGENE00001429
caenorhabditis_elegans	fkb-5	WBGENE00001430

Paralogs (18): FKBP4 (ENSG00000004478), FKBP6 (ENSG00000077800), FKBP7 (ENSG00000079150), FKBP1A (ENSG00000088832), FKBP5 (ENSG00000096060), FKBP3 (ENSG00000100442), FKBP8 (ENSG00000105701), FKBP15 (ENSG00000119321), FKBP1B (ENSG00000119782), FKBP9 (ENSG00000122642), TTC9 (ENSG00000133985), FKBP11 (ENSG00000134285), FKBP10 (ENSG00000141756), TTC9C (ENSG00000162222), FKBP2 (ENSG00000173486), TTC9B (ENSG00000174521), FKBP1C (ENSG00000198225), FKBPL (ENSG00000204315)

Protein

Protein identifiers

Peptidyl-prolyl cis-trans isomerase FKBP14 — Q9NWM8 (reviewed: Q9NWM8)

Alternative names: 22 kDa FK506-binding protein, FK506-binding protein 14, Rotamase

All UniProt accessions (4): Q9NWM8, A0A090N7V8, F8WBZ0, H7C1Z9

UniProt curated annotations — full annotation on UniProt →

Function. PPIase which accelerates the folding of proteins during protein synthesis. Has a preference for substrates containing 4-hydroxylproline modifications, including type III collagen. May also target type VI and type X collagens.

Subunit / interactions. Monomer. Homodimer. Interacts with type III, type IV and type X collagens.

Subcellular location. Endoplasmic reticulum lumen.

Disease relevance. Ehlers-Danlos syndrome, kyphoscoliotic type, 2 (EDSKSCL2) [MIM:614557] A form of Ehlers-Danlos syndrome, a group of connective tissue disorders characterized by skin hyperextensibility, articular hypermobility, and tissue fragility. EDSKSCL2 is an autosomal recessive form characterized by severe generalized hypotonia at birth, myopathy, early-onset progressive kyphoscoliosis, joint hypermobility without contractures, hyperelastic skin with follicular hyperkeratosis, easy bruising, and occasional abnormal scarring, sensorineural hearing impairment, and normal pyridinoline excretion in urine. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by tacrolimus/FK506.

RefSeq proteins (1): NP_060416* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001179	PPIase_FKBP_dom	Domain
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR046357	PPIase_dom_sf	Homologous_superfamily
IPR052273	PPIase_FKBP	Family

Pfam: PF00254

Enzyme classification (BRENDA):

• EC 5.2.1.8 — peptidylprolyl isomerase (BRENDA: 69 organisms, 374 substrates, 222 inhibitors, 24 Km, 30 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
N-SUCCINYL-ALA-GLU-(TRANS)-PRO-PHE-4-NITROANILID	0.17–0.7	5
N-SUCCINYL-ALA-ALA-(CIS)-PRO-PHE-4-NITROANILIDE	0.104–0.814	2
RNASE T1	0.0004–0.0006	2
SUCCINYL-ALA-ALA-PRO-PHE 4-NITROANILIDE	0.451–1.247	2
SUCCINYL-ALA-LYS-PRO-PHE-4-NITROANILIDE	0.585–0.788	2
ALA-GLY-PSI[CS-N]-PRO-PHE-4-NITROANILIDE	0.53	1
N-SUCCINYL-ALA-LEU-(CIS)-PRO-PHE-4-NITROANILIDE	0.059	1
SUCCINYL-ALA-GLU-PRO-PHE-7-AMIDO-4-METHYLCOUMARI	0.12	1
TRYWNAKMK-(CIS)-PFIFGA	2	1
SUCCINYL-ALA-ALA-(CIS)-PRO-LYS-4-METHYLCOUMARIN-	—	0
SUCCINYL-ALA-ALA-(CIS)-PRO-PHE 4-METHYLCOUMARIN	—	0

Catalyzed reactions (Rhea), 1 shown:

• [protein]-peptidylproline (omega=180) = [protein]-peptidylproline (omega=0) (RHEA:16237)

UniProt features (38 total): binding site 10, helix 8, strand 8, turn 4, domain 3, signal peptide 1, chain 1, glycosylation site 1, disulfide bond 1, short sequence motif 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4DIP	X-RAY DIFFRACTION	1.82
4MSP	X-RAY DIFFRACTION	1.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NWM8-F1	88.27	0.67

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 (10): 159; 192; 194; 196; 198; 203; 148; 150; 152; 154

Disulfide bonds (1): 38–96

Glycosylation sites (1): 176

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-381038	XBP1(S) activates chaperone genes

MSigDB gene sets: 246 (showing top): REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, MODULE_205, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, HTF_01, DODD_NASOPHARYNGEAL_CARCINOMA_UP, AP2_Q6_01, AP2GAMMA_01, FOX_Q2, VECCHI_GASTRIC_CANCER_ADVANCED_VS_EARLY_UP, GOCC_ENDOPLASMIC_RETICULUM_LUMEN, GOMF_CIS_TRANS_ISOMERASE_ACTIVITY, AP2_Q6, XBP1_01

GO Biological Process (0):

GO Molecular Function (5): peptidyl-prolyl cis-trans isomerase activity (GO:0003755), calcium ion binding (GO:0005509), protein binding (GO:0005515), isomerase activity (GO:0016853), metal ion binding (GO:0046872)

GO Cellular Component (2): endoplasmic reticulum lumen (GO:0005788), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
IRE1alpha activates chaperones	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cis-trans isomerase activity	1
catalytic activity, acting on a protein	1
metal ion binding	1
binding	1
catalytic activity	1
cation binding	1
endoplasmic reticulum	1
intracellular organelle lumen	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2096 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FKBP14	PLOD1	Q02809	679
FKBP14	CHST14	Q8NCH0	663
FKBP14	SLC39A13	Q96H72	641
FKBP14	B4GALT7	Q9UBV7	625
FKBP14	ZNF469	Q96JG9	605
FKBP14	B3GALT6	Q96L58	605
FKBP14	COL3A1	P02461	591
FKBP14	TNXB	P22105	570
FKBP14	PRDM5	Q9NQX1	558
FKBP14	ADAMTS2	O95450	522
FKBP14	COL1A1	P02452	513
FKBP14	SYVN1	Q86TM6	508
FKBP14	COL5A1	P20908	507
FKBP14	RSPRY1	Q96DX4	489
FKBP14	COL5A2	P05997	486

IntAct

89 interactions, top by confidence:

A	B	Type	Score
H4C16	HAT1	psi-mi:“MI:0914”(association)	0.700
SERPINA4	FKBP14	psi-mi:“MI:0915”(physical association)	0.690
ERLIN2	HSPA5	psi-mi:“MI:0914”(association)	0.640
BNIP1	NBAS	psi-mi:“MI:0914”(association)	0.640
TMEM237	FKBP14	psi-mi:“MI:0915”(physical association)	0.560
FUT9	FKBP14	psi-mi:“MI:0915”(physical association)	0.560
SUN2	POTEF	psi-mi:“MI:0914”(association)	0.530
S1PR2	PALM3	psi-mi:“MI:0914”(association)	0.530
DEFA5	NUDT19	psi-mi:“MI:0914”(association)	0.530
TRHDE	MAN1A2	psi-mi:“MI:0914”(association)	0.530
FUT3	C1QL1	psi-mi:“MI:0914”(association)	0.530
GNS	CLPX	psi-mi:“MI:0914”(association)	0.530
ST3GAL2	HSPA5	psi-mi:“MI:0914”(association)	0.530
SPACA3	HSPA5	psi-mi:“MI:0914”(association)	0.530
ELSPBP1	PFDN1	psi-mi:“MI:0914”(association)	0.530
DHH	HSPA5	psi-mi:“MI:0914”(association)	0.530
POMGNT2	PECR	psi-mi:“MI:0914”(association)	0.530
ARSK	CANX	psi-mi:“MI:0914”(association)	0.530
SUN2	PIP4K2A	psi-mi:“MI:0914”(association)	0.530
SUN2	PIP	psi-mi:“MI:0914”(association)	0.530

BioGRID (111): FKBP14 (Affinity Capture-MS), FKBP14 (Affinity Capture-MS), FKBP14 (Affinity Capture-MS), FKBP14 (Affinity Capture-MS), FKBP14 (Affinity Capture-MS), FKBP14 (Affinity Capture-MS), FKBP14 (Co-fractionation), HSPA4L (Co-fractionation), LCP1 (Co-fractionation), PLS1 (Co-fractionation), PPA2 (Co-fractionation), FKBP14 (Affinity Capture-MS), FKBP14 (Affinity Capture-MS), FKBP14 (Affinity Capture-MS), FKBP14 (Affinity Capture-MS)

ESM2 similar proteins: H0ZAB5, O35548, O46638, O54998, O61394, O73798, O77636, P0C1J4, P0C1J5, P0CP96, P0CP97, P26884, P29120, P32472, P34714, P45878, P51512, P59024, P63239, P63240, P70419, P78536, Q00688, Q14435, Q19267, Q32PA9, Q38935, Q38936, Q41649, Q5BKL9, Q5R941, Q5RET2, Q5RF88, Q5ZKE5, Q62446, Q66JA6, Q6CGG3, Q6CUZ8, Q6FSC1, Q6WV20

Diamond homologs: F4J9Q6, G0SC91, O46638, O54998, O60046, O74191, O94746, O95302, P0A0W2, P0A0W3, P0C1B0, P0C1J3, P0C1J4, P0C1J5, P0C1J6, P0CP94, P0CP95, P0CP96, P0CP97, P0CP98, P0CP99, P18203, P20080, P20081, P26883, P26884, P26885, P28725, P32472, P38911, P45878, P48375, P54397, P56989, P59024, P62942, P62943, P68106, P68107, P97534

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 103 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.

GO biological processes:

GO term	Partners	Fold	FDR
ERAD pathway	6	11.7×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	4
Uncertain significance	110
Likely benign	66
Benign	8

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
1068632	NM_017946.4(FKBP14):c.95_96del (p.Leu32fs)	Pathogenic
1433477	NM_017946.4(FKBP14):c.206dup (p.His69fs)	Pathogenic
2739931	NM_017946.4(FKBP14):c.264G>A (p.Trp88Ter)	Pathogenic
4025182	NM_017946.4(FKBP14):c.181del (p.Ser61fs)	Pathogenic
4722553	NM_017946.4(FKBP14):c.364G>T (p.Glu122Ter)	Pathogenic
567476	NM_017946.4(FKBP14):c.156T>A (p.Tyr52Ter)	Pathogenic
599393	NM_017946.4(FKBP14):c.570AGA[1] (p.Glu191del)	Pathogenic
657045	NM_017946.4(FKBP14):c.34_35del (p.Leu12fs)	Pathogenic
807418	NM_017946.4(FKBP14):c.636G>C (p.Ter212Tyr)	Pathogenic
161456	NM_017946.4(FKBP14):c.197+5_197+8del	Likely pathogenic
2501231	NM_017946.4(FKBP14):c.52_55del (p.Ile18fs)	Likely pathogenic
3654395	NM_017946.4(FKBP14):c.349+1G>A	Likely pathogenic
944682	NM_017946.4(FKBP14):c.197+1G>A	Likely pathogenic

SpliceAI

765 predictions. Top by Δscore:

Variant	Effect	Δscore
7:30014689:C:A	donor_gain	1.0000
7:30014744:AT:A	donor_gain	1.0000
7:30014745:T:C	donor_gain	1.0000
7:30014784:T:C	donor_gain	1.0000
7:30018342:C:CA	donor_gain	1.0000
7:30018351:T:TA	donor_gain	1.0000
7:30018997:T:TA	donor_gain	1.0000
7:30019000:T:C	donor_gain	1.0000
7:30019128:CG:C	acceptor_gain	1.0000
7:30022812:TGTGA:T	acceptor_gain	1.0000
7:30022814:TGA:T	acceptor_gain	1.0000
7:30022817:C:CC	acceptor_gain	1.0000
7:30026306:ACTT:A	donor_loss	1.0000
7:30026308:TTACG:T	donor_loss	1.0000
7:30026309:TACGT:T	donor_loss	1.0000
7:30026310:A:AC	donor_gain	1.0000
7:30026310:ACGTG:A	donor_loss	1.0000
7:30026311:C:CA	donor_gain	1.0000
7:30026311:CG:C	donor_gain	1.0000
7:30026311:CGT:C	donor_gain	1.0000
7:30026311:CGTG:C	donor_gain	1.0000
7:30026311:CGTGG:C	donor_gain	1.0000
7:30026333:T:TA	donor_gain	1.0000
7:30014732:T:C	donor_gain	0.9900
7:30014740:A:C	donor_gain	0.9900
7:30014744:A:AC	donor_gain	0.9900
7:30018338:ATCTC:A	donor_gain	0.9900
7:30018423:T:TA	donor_gain	0.9900
7:30018990:GGTCA:G	donor_loss	0.9900
7:30018991:GTCAC:G	donor_loss	0.9900

AlphaMissense

1407 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:30022706:A:G	L103P	0.999
7:30014759:A:C	F204L	0.998
7:30014759:A:T	F204L	0.998
7:30014761:A:G	F204L	0.998
7:30019009:A:G	L155P	0.998
7:30019041:G:C	F144L	0.998
7:30019041:G:T	F144L	0.998
7:30019042:A:C	F144C	0.998
7:30019042:A:G	F144S	0.998
7:30019043:A:G	F144L	0.998
7:30019099:A:G	L125P	0.998
7:30022727:C:G	C96S	0.998
7:30022728:A:T	C96S	0.998
7:30022752:A:G	W88R	0.998
7:30022752:A:T	W88R	0.998
7:30014760:A:C	F204C	0.997
7:30019009:A:T	L155H	0.997
7:30022728:A:G	C96R	0.997
7:30026396:C:G	C38S	0.997
7:30026397:A:G	C38R	0.997
7:30026397:A:T	C38S	0.997
7:30014760:A:G	F204S	0.996
7:30014775:A:T	I199K	0.996
7:30019031:C:G	D148H	0.996
7:30019081:A:G	L131P	0.996
7:30019093:A:G	F127S	0.996
7:30022726:A:C	C96W	0.996
7:30022727:C:T	C96Y	0.996
7:30022755:C:G	G87R	0.996
7:30026360:A:T	V50D	0.996

dbSNP variants (sampled 300 via entrez): RS1000340731 (7:30016741 A>C), RS1000507183 (7:30022135 A>C), RS1000523493 (7:30010667 T>C,G), RS1000576741 (7:30017001 T>A), RS1000576763 (7:30028443 C>T), RS1000900771 (7:30005909 T>C), RS1000964009 (7:30016585 G>A,T), RS1000979218 (7:30010324 C>T), RS1001108556 (7:30023754 G>A), RS1001135874 (7:30007775 G>A), RS1001566414 (7:30022169 A>G), RS1001624315 (7:30027549 T>C), RS1001638645 (7:30022519 C>G,T), RS1001680031 (7:30014004 C>T), RS1001692324 (7:30014303 C>T)

Disease associations

OMIM: gene MIM:614505 | disease phenotypes: MIM:614557, MIM:130000

GenCC curated gene-disease

Disease	Classification	Inheritance
Ehlers-Danlos syndrome, kyphoscoliotic type, 2	Definitive	Autosomal recessive

Mondo (3): Ehlers-Danlos syndrome, kyphoscoliotic type, 2 (MONDO:0013800), Ehlers-Danlos syndrome (MONDO:0020066), congenital muscular dystrophy (MONDO:0019950)

Orphanet (3): Kyphoscoliotic Ehlers-Danlos syndrome due to FKBP22 deficiency (Orphanet:300179), Ehlers-Danlos syndrome (Orphanet:98249), Congenital muscular dystrophy (Orphanet:97242)

HPO phenotypes

55 total (30 of 55 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000015	Bladder diverticulum
HP:0000023	Inguinal hernia
HP:0000185	Cleft soft palate
HP:0000286	Epicanthus
HP:0000340	Sloping forehead
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000410	Mixed hearing impairment
HP:0000482	Microcornea
HP:0000545	Myopia
HP:0000592	Blue sclerae
HP:0000601	Hypotelorism
HP:0000938	Osteopenia
HP:0000973	Cutis laxa
HP:0000974	Hyperextensible skin
HP:0000977	Soft skin
HP:0000978	Bruising susceptibility
HP:0001075	Atrophic scars
HP:0001252	Hypotonia
HP:0001270	Motor delay
HP:0001319	Neonatal hypotonia
HP:0001324	Muscle weakness
HP:0001382	Joint hypermobility
HP:0001519	Disproportionate tall stature
HP:0001537	Umbilical hernia
HP:0001558	Decreased fetal movement
HP:0001561	Polyhydramnios
HP:0001643	Patent ductus arteriosus
HP:0001653	Mitral regurgitation

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001553_1	Estradiol levels	2.000000e-06
GCST009268_11	Dental caries (decayed, missing and filled tooth surfaces)	7.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004697	estradiol measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D004535	Ehlers-Danlos Syndrome	C14.907.454.240; C15.378.463.515.240; C16.131.831.428; C16.320.850.260; C17.300.200.310; C17.800.804.428; C17.800.827.260

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2342 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 39,732 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL123292	CYCLOHEXIMIDE	2	39,732

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases methylation	7
Cyclosporine	increases expression	4
trichostatin A	affects cotreatment, increases expression	3
bisphenol A	decreases expression, affects cotreatment, affects expression, increases abundance	2
Benzo(a)pyrene	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
aristolochic acid I	decreases expression	1
ginger extract	affects cotreatment, affects expression, increases abundance	1
methylmercuric chloride	increases expression	1
beta-lapachone	increases expression	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
beta-methylcholine	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	decreases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
pyrachlostrobin	decreases expression	1
dorsomorphin	increases expression, affects cotreatment	1
picoxystrobin	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Vorinostat	affects cotreatment, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL682335	Binding	Inhibition constant(Ki) for inhibition of PPIase activity of Photobacterium sp. FK506 binding protein 22 (Conc=41 nM) of FKBPs family	Synthesis and cytotoxic evaluation of cycloheximide derivatives as potential inhibitors of FKBP12 with neuroregenerative properties. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04890431	PHASE4	UNKNOWN	Impact of Oxygen Therapy on Fatigue in Patients With Hypermobile-type Ehlers-Danlos Syndrome
NCT05603741	PHASE4	ACTIVE_NOT_RECRUITING	Local Anesthetic Response in Ehlers-Danlos Syndrome (EDS) and Healthy Volunteers
NCT01422200	PHASE4	COMPLETED	Flu Vaccine Study in Neuromuscular Patients 2011
NCT05279937	PHASE3	NOT_YET_RECRUITING	The Ultrasound-Guided Dextrose Prolotherapy in Ehlers-Danlos Syndrome Patients
NCT00001966	PHASE2	COMPLETED	Mind-Body Therapy for Pain in Ehlers-Danlos Syndrome
NCT01805024	PHASE1	COMPLETED	Congenital Muscular Dystrophy Ascending Multiple Dose Cohort Study Analyzing Pharmacokinetics at Three Dose Levels In Children and Adolescents With Assessment of Safety and Tolerability of Omigapil (CALLISTO)
NCT03686748	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Two Point Discrimination
NCT00001641	Not specified	COMPLETED	Study of Heritable Connective Tissue Disorders
NCT00270686	Not specified	COMPLETED	Studies of Heritable Disorders of Connective Tissue
NCT01322165	Not specified	COMPLETED	National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions
NCT01356134	Not specified	COMPLETED	Vascular Fundus Changes in Patients With High Probability of Chronic Cerebrospinal Venous Insufficiency (CCSVI)
NCT01367977	Not specified	COMPLETED	Head Circumference Growth in Children With Ehlers-Danlos Syndrome Who Develop Dysautonomia Later in Life
NCT02050113	Not specified	RECRUITING	Complex Aortic Aneurysm Repair Using Physician Modified Endografts and Custom Made Devices
NCT02435745	Not specified	COMPLETED	Obstructive Sleep Apnoea in Ehlers-Danlos Syndrome
NCT02721797	Not specified	UNKNOWN	Origins and Impact of EDS in Connective Tissues and Skin
NCT02985710	Not specified	COMPLETED	Assessment of Small Fiber Neuropathy in Rare Diseases Using Sudoscan
NCT03093493	Not specified	COMPLETED	Genetics of Ehlers-Danlos Syndrome
NCT03330977	Not specified	UNKNOWN	Efficiency Clinical Study of NOVATEX MEDICAL Compression Garments in Patients With Ehlers-Danlos Syndrome
NCT03575182	Not specified	UNKNOWN	Gait Retraining in Patients With Joint Hypermobility Syndrome/Hypermobile Ehlers Danlos Syndrome
NCT03596437	Not specified	UNKNOWN	Study of Arterial Properties by Ultra-high Frequency Ultrasound in Fibromuscular Dysplasia and Vascular Ehlers-Danlos Syndrome
NCT03602482	Not specified	COMPLETED	Standing Cognition and Co-morbidities of POTS Evaluation
NCT03681080	Not specified	COMPLETED	Concentration and Attentional Deficits in POTS and Other Autonomic Neuropathies
NCT03986229	Not specified	COMPLETED	Evaluation of the Effect of Custom Compression Garments on Standing Static Balance in Ehlers Danlos Syndrome
NCT04036305	Not specified	ACTIVE_NOT_RECRUITING	Local Anesthetic Response in Ehlers-Danlos Syndrome (EDS) and Healthy Volunteers
NCT04133272	Not specified	RECRUITING	Registry of Ehlers-Danlos Syndrome
NCT04437589	Not specified	COMPLETED	Opioid-Free Anesthesia for Patients With Joint Hypermobility Syndrome Undergoing Craneo-Cervical Fixation: A Case-series
NCT04680793	Not specified	COMPLETED	Effects of a Multidisciplinary Outpatient Rehabilitation Program in Patients With Ehlers-Danlos Syndrome.
NCT04734041	Not specified	COMPLETED	Integrative Medicine for Hypermobility Spectrum Disorder and Ehlers-Danlos Syndromes (IMforHSDandEDS)
NCT04742803	Not specified	COMPLETED	Straberi Epistamp Needling Treatment For Skin Rejuvenation
NCT04806620	Not specified	RECRUITING	Unhide® Project: A Digital Health Platform to Collect Lifestyle Data for Brain Inflammation Research
NCT05137379	Not specified	COMPLETED	Evaluation of a Cohort of Patients With Ehlers-Danlos Syndrome Treated With Orthopedic Surgery (SED-eval)
NCT05366114	Not specified	UNKNOWN	Vision-based Assessment of Joint Extensibility in Ehlers Danlos Syndrome
NCT05389865	Not specified	ACTIVE_NOT_RECRUITING	Proximal Aortopathy in Scotland - Epidemiology and Surgical Outcomes
NCT05429996	Not specified	UNKNOWN	Ultrastructural Collagen Markers in Ehlers Danlos Syndromes
NCT05434728	Not specified	UNKNOWN	Characterization of Bleeding Disorders in EDS
NCT05516043	Not specified	COMPLETED	Safety and Performance of POLYTHESE® Vascular Prosthesis
NCT05561270	Not specified	RECRUITING	Light Exposure on Pain in Hypermobile Ehlers-Danlos Syndrome
NCT05720923	Not specified	ACTIVE_NOT_RECRUITING	Analysis of Muscular Properties in Patients With MFS and EDS
NCT05871216	Not specified	RECRUITING	Functional Instability in Patients Suffering From Collagen Disease and Joint Hypermobility
NCT05945784	Not specified	COMPLETED	Exploring Accessible Beauty for Individuals With Upper Extremity Deficits