PHLDB1

Summary

PHLDB1 (pleckstrin homology like domain family B member 1, HGNC:23697) is a protein-coding gene on chromosome 11q23.3, encoding Pleckstrin homology-like domain family B member 1 (Q86UU1).

Involved in regulation of embryonic development; regulation of epithelial to mesenchymal transition; and regulation of microtubule cytoskeleton organization. Located in basal cortex. Implicated in osteogenesis imperfecta.

Source: NCBI Gene 23187 — RefSeq curated summary.

At a glance

• Gene–disease (curated): osteogenesis imperfecta, type 23 (Moderate, GenCC)
• GWAS associations: 25
• Clinical variants (ClinVar): 240 total — 2 pathogenic
• Phenotypes (HPO): 16
• Druggable target: yes
• MANE Select transcript: NM_001144758

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23697
Approved symbol	PHLDB1
Name	pleckstrin homology like domain family B member 1
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ00141, LL5a, KIAA0638
Ensembl gene	ENSG00000019144
Ensembl biotype	protein_coding
OMIM	612834
Entrez	23187

Gene structure

Transcript identifiers

Ensembl transcripts: 76 — 54 protein_coding, 10 retained_intron, 10 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000356063, ENST00000361417, ENST00000392852, ENST00000524713, ENST00000525226, ENST00000525427, ENST00000526374, ENST00000526537, ENST00000526699, ENST00000526826, ENST00000527259, ENST00000527500, ENST00000527898, ENST00000528594, ENST00000528875, ENST00000529005, ENST00000530994, ENST00000531987, ENST00000532517, ENST00000532639, ENST00000534140, ENST00000600882, ENST00000612681, ENST00000614369, ENST00000617208, ENST00000620788, ENST00000621027, ENST00000860941, ENST00000860942, ENST00000860943, ENST00000860944, ENST00000860945, ENST00000860946, ENST00000860947, ENST00000860948, ENST00000860949, ENST00000860950, ENST00000860951, ENST00000860952, ENST00000860953, ENST00000860954, ENST00000860955, ENST00000860956, ENST00000860957, ENST00000860958, ENST00000860959, ENST00000860960, ENST00000860961, ENST00000860962, ENST00000860963, ENST00000860964, ENST00000860965, ENST00000860966, ENST00000860967, ENST00000860968, ENST00000860969, ENST00000860970, ENST00000860971, ENST00000860972, ENST00000860973, ENST00000860974, ENST00000860975, ENST00000860976, ENST00000860977, ENST00000860978, ENST00000860979, ENST00000860980, ENST00000860981, ENST00000860982, ENST00000860983, ENST00000860984, ENST00000860985, ENST00000860986, ENST00000860987, ENST00000860988, ENST00000969923

RefSeq mRNA: 3 — MANE Select: NM_001144758 NM_001144758, NM_001144759, NM_015157

CCDS: CCDS44750, CCDS8401

Canonical transcript exons

ENST00000600882 — 23 exons

Exon	Start	End
ENSE00002198807	118607615	118607699
ENSE00002987228	118632159	118632296
ENSE00003030169	118656683	118658028
ENSE00003132930	118627305	118628650
ENSE00003169889	118631913	118632053
ENSE00003185331	118631207	118631479
ENSE00003711537	118624934	118625059
ENSE00003714567	118635393	118635548
ENSE00003721761	118638891	118639001
ENSE00003724995	118655860	118655892
ENSE00003728463	118647930	118648076
ENSE00003733801	118655605	118655690
ENSE00003735708	118643800	118643940
ENSE00003736272	118645356	118645650
ENSE00003737315	118639162	118639251
ENSE00003740739	118645735	118645825
ENSE00003743963	118644072	118644174
ENSE00003744205	118650077	118650193
ENSE00003745519	118613816	118613896
ENSE00003747379	118616041	118616211
ENSE00003747386	118650445	118650547
ENSE00003753165	118642254	118642394
ENSE00003754879	118614559	118614682

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 99.29.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.1613 / max 759.8381, expressed in 1690 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117021	17.8042	1388
117032	13.5812	1582
117020	2.3857	1037
117033	1.5046	846
117039	0.4481	153
206469	0.4123	222
117037	0.3562	191
117029	0.2833	150
117035	0.1833	56
117030	0.1054	52

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	99.29	gold quality
tibial nerve	UBERON:0001323	98.87	gold quality
middle frontal gyrus	UBERON:0002702	98.58	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.51	gold quality
metanephros cortex	UBERON:0010533	98.51	gold quality
apex of heart	UBERON:0002098	98.50	gold quality
mucosa of stomach	UBERON:0001199	98.48	gold quality
endocervix	UBERON:0000458	98.23	gold quality
left uterine tube	UBERON:0001303	98.23	gold quality
corpus callosum	UBERON:0002336	98.01	gold quality
spinal cord	UBERON:0002240	97.98	gold quality
body of uterus	UBERON:0009853	97.98	gold quality
omental fat pad	UBERON:0010414	97.96	gold quality
peritoneum	UBERON:0002358	97.95	gold quality
right atrium auricular region	UBERON:0006631	97.86	gold quality
subcutaneous adipose tissue	UBERON:0002190	97.70	gold quality
adipose tissue of abdominal region	UBERON:0007808	97.56	gold quality
stromal cell of endometrium	CL:0002255	97.54	gold quality
right lung	UBERON:0002167	97.54	gold quality
right ovary	UBERON:0002118	97.39	gold quality
right coronary artery	UBERON:0001625	97.38	gold quality
ascending aorta	UBERON:0001496	97.21	gold quality
thoracic aorta	UBERON:0001515	97.20	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.20	gold quality
coronary artery	UBERON:0001621	97.18	gold quality
left coronary artery	UBERON:0001626	97.15	gold quality
putamen	UBERON:0001874	97.13	gold quality
colonic epithelium	UBERON:0000397	97.07	gold quality
inferior vagus X ganglion	UBERON:0005363	97.05	gold quality
amygdala	UBERON:0001876	97.02	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.50

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

78 targeting PHLDB1, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-379-3P	99.69	69.60	1524
HSA-MIR-411-3P	99.69	69.63	1524
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-7156-5P	99.64	68.81	1369
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-6861-3P	99.60	68.46	444
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-4708-3P	99.51	67.99	870

Literature-anchored findings (GeneRIF, showing 16)

• Signaling from laminin-integrin associations in epithelial cells attaches microtubule plus ends to the epithelial basal cell cortex via PHLDB1 and PHLDB2. (PMID:20513769)
• SUSCEPTIBILITY LOCI FOR GLIOMA AND GLIOBLASTOMA RISK IN A CHINESE POPULATION INCLUDED PHLDBI (PMID:21350045)
• Single nucleotide polymorphisms in the PHLDB1 and ARCN1 genes are associated with increased risk of Glioma. (PMID:23300798)
• study discovered multiple susceptibility variants for systemic lupus erythematosus in the 11q23.3 region, including variants in/near PHLDB1 (rs11603023), DDX6 (rs638893) and CXCR5 (rs10892301) (PMID:24001599)
• PHLDB1 rs498872 polymorphism was associated with increased risk of glioma. (PMID:24935770)
• Liprin-alpha1, ERC1a and LL5 also define new highly polarized and dynamic cytoplasmic structures uniquely localized near the protruding cell edge (PMID:24982445)
• results suggest a significant association between the RETL1, TREH, and PHLDB1 genes and GBM development in the Han Chinese population (PMID:26156397)
• Functional analysis of the 11q23.3 glioma susceptibility locus implicates PHLDB1 and DDX6 in glioma susceptibility. (PMID:26610392)
• The rs498872 PHLDB1 polymorphism was significantly associated with glioma risk in Chinese Han population. (PMID:28886307)
• The results indicate that liprin-alpha1, LL5 and ERC1 define a novel dynamic membrane-less compartment that regulates matrix degradation by affecting invadosome motility. (PMID:29348417)
• findings suggest that genetic variation of PHLDB1 may be associated with the risk of nonfunctional pituitary adenoma (PMID:30868356)
• this paper shows that PHLDB1 gene polymorphism is associated with IgA nephropathy risk in Chinese Han population (PMID:30928649)
• Role of Polymorphisms of FAM13A, PHLDB1, and CYP24A1 in Breast Cancer Risk. (PMID:31215377)
• The rs6010620 (RTEL1), rs4977756 (CDKN2A/B), and rs498872 (PHLDB1) are associated with glioma risk in the Portuguese population. The GA genotype of the rs498872 (PHLDB1) was associated with an increased risk of gliomas (OR 2.92) and glioblastomas (OR 2.39). In addition, the genotype AA of the rs498872 (PHLDB1) was associated with poor overall survival of gliomas patients (AA vs. GA, p = 0.037). (PMID:31721021)
• Analysis of WDFY4 rs7097397 and PHLDB1 rs7389 polymorphisms in Chinese patients with systemic lupus erythematosus. (PMID:35188604)
• Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes. (PMID:36543534)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	phldb1a	ENSDARG00000061093
danio_rerio	phldb1b	ENSDARG00000079378
mus_musculus	Phldb1	ENSMUSG00000048537
rattus_norvegicus	Phldb1	ENSRNOG00000026985
drosophila_melanogaster	dos	FBGN0016794
caenorhabditis_elegans		WBGENE00004928

Paralogs (7): GAB2 (ENSG00000033327), GAB1 (ENSG00000109458), PHLDB2 (ENSG00000144824), PLEKHS1 (ENSG00000148735), GAB3 (ENSG00000160219), PHLDB3 (ENSG00000176531), GAB4 (ENSG00000215568)

Protein

Protein identifiers

Pleckstrin homology-like domain family B member 1 — Q86UU1 (reviewed: Q86UU1)

Alternative names: Protein LL5-alpha

All UniProt accessions (3): A0A087WTZ7, A0A087WZL0, Q86UU1

UniProt curated annotations — full annotation on UniProt →

Disease relevance. Osteogenesis imperfecta 23 (OI23) [MIM:620639] An autosomal recessive form of osteogenesis imperfecta, a disorder of bone formation characterized by low bone mass, bone fragility and susceptibility to fractures after minimal trauma. Disease severity ranges from very mild forms without fractures to intrauterine fractures and perinatal lethality. Extraskeletal manifestations, which affect a variable number of patients, are dentinogenesis imperfecta, hearing loss, and blue sclerae. OI23 is a mild form characterized by osteopenia with or without recurrent fractures, platyspondyly, short and bowed long bones, and widened metaphyses. Platyspondyly and metaphyseal enlargement is present in infancy but resolve in middle childhood. The disease may be caused by variants affecting the gene represented in this entry.

Domain organisation. The PH domain mediates the binding to phosphoinositides.

Miscellaneous. Minor. Major.

Isoforms (3)

UniProt ID	Names	Canonical?
Q86UU1-1	1	yes
Q86UU1-2	2
Q86UU1-3	3

RefSeq proteins (3): NP_001138230, NP_001138231, NP_055972 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000253	FHA_dom	Domain
IPR001849	PH_domain	Domain
IPR008984	SMAD_FHA_dom_sf	Homologous_superfamily
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR037810	PHLDB1/2/3_PH	Domain
IPR052212	PH-like_domain	Family

Pfam: PF00169, PF00498

UniProt features (54 total): modified residue 29, compositionally biased region 10, region of interest 6, splice variant 4, domain 2, coiled-coil region 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86UU1-F1	60.40	0.19

Functional residue map

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

Post-translational modifications (29): 51, 131, 192, 220, 223, 324, 334, 381, 404, 430, 443, 461, 470, 489, 501, 512, 518, 520, 522, 533 …

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 262 (showing top): BENPORATH_ES_WITH_H3K27ME3, MORF_MSH3, MORF_BRCA1, AP4_Q6, HNF1_Q6, CAGCTG_AP4_Q5, MORF_RAD51L3, GTGCCTT_MIR506, WATANABE_RECTAL_CANCER_RADIOTHERAPY_RESPONSIVE_UP, FOSTER_TOLERANT_MACROPHAGE_UP, MORF_IL4, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, MORF_PRKCA, LANDIS_ERBB2_BREAST_TUMORS_65_DN, GALINDO_IMMUNE_RESPONSE_TO_ENTEROTOXIN

GO Biological Process (1): basement membrane organization (GO:0071711)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (1): basal cortex (GO:0045180)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
extracellular matrix organization	1
binding	1
basal part of cell	1
cell cortex region	1

Protein interactions and networks

STRING

612 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PHLDB1	RTEL1	Q9NZ71	767
PHLDB1	PLEK	P08567	613
PHLDB1	TERT	O14746	573
PHLDB1	CDKN2B	P42772	571
PHLDB1	TREH	O43280	563
PHLDB1	ANKRD35	Q8N283	499
PHLDB1	TMEM25	Q86YD3	447
PHLDB1	C2orf80	Q0P641	433
PHLDB1	DDX6	P26196	431
PHLDB1	DCTN2	Q13561	423
PHLDB1	CDKN2A	P42771	398
PHLDB1	FOXR1	Q6PIV2	391
PHLDB1	EGFR	P00533	372
PHLDB1	ARCN1	P48444	358
PHLDB1	COBLL1	Q53SF7	355

IntAct

49 interactions, top by confidence:

A	B	Type	Score
PHLDB1	FXR2	psi-mi:“MI:0915”(physical association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
FXR2	CSNK2A1	psi-mi:“MI:0914”(association)	0.640
PPP2R3A	WTIP	psi-mi:“MI:0914”(association)	0.640
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
PNMA2	CCDC85C	psi-mi:“MI:0914”(association)	0.530
PHLDB1	FXR1	psi-mi:“MI:0915”(physical association)	0.510
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
PHLDB1	RPS25	psi-mi:“MI:0915”(physical association)	0.400
PHLDB1	MKI67	psi-mi:“MI:0915”(physical association)	0.400
PHLDB1	SHANK3	psi-mi:“MI:0915”(physical association)	0.370
PHLDB1	TSC1	psi-mi:“MI:0915”(physical association)	0.370
PHLDB1	TSC2	psi-mi:“MI:0915”(physical association)	0.370
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
EGLN3	FAM168B	psi-mi:“MI:0914”(association)	0.350
	AGPS	psi-mi:“MI:0914”(association)	0.350
CDK5RAP2	PDHX	psi-mi:“MI:0914”(association)	0.350
CDK5RAP2	SPTBN2	psi-mi:“MI:0914”(association)	0.350
RIMS1	KIF2A	psi-mi:“MI:0914”(association)	0.350
YWHAE	DEPDC5	psi-mi:“MI:0914”(association)	0.350
VCP	FAM171A2	psi-mi:“MI:0914”(association)	0.350
DDX28	UBA6	psi-mi:“MI:0914”(association)	0.350
FTL		psi-mi:“MI:0914”(association)	0.350
PHAF1	ARHGAP32	psi-mi:“MI:0914”(association)	0.350
RAE1	NHERF1	psi-mi:“MI:0914”(association)	0.350

BioGRID (61): PHLDB1 (Affinity Capture-MS), PHLDB1 (Affinity Capture-MS), PHLDB1 (Biochemical Activity), PHLDB1 (Affinity Capture-MS), PHLDB1 (Affinity Capture-MS), PHLDB1 (Affinity Capture-MS), PHLDB1 (Affinity Capture-MS), PHLDB1 (Affinity Capture-RNA), PHLDB1 (Affinity Capture-MS), PHLDB1 (Affinity Capture-MS), PHLDB1 (Proximity Label-MS), PHLDB1 (Proximity Label-MS), PHLDB1 (Proximity Label-MS), PHLDB1 (Proximity Label-MS), PHLDB1 (Affinity Capture-MS)

ESM2 similar proteins: A0A8I3QA39, A1YB07, A2A6T1, A2A9T0, A2AHG0, A5PKL7, A6NKD9, A7MCY6, B8A5S6, D3ZD05, E1BEQ5, E1U8D0, E9Q6B2, F1MRK3, G3V735, O14529, O60299, O75145, O94964, P60469, Q1LZH7, Q3LUD4, Q3UIL6, Q499E4, Q5JTD0, Q5RCR6, Q5XIA0, Q62036, Q63ZY3, Q6DG50, Q6IQ23, Q6NZT2, Q6PDH0, Q86UU1, Q86X02, Q8BX02, Q8C7U1, Q8IY63, Q8K1Q4, Q8K371

Diamond homologs: A0A0G2JXT6, A2BGG1, A4FU01, A7MB43, E9PXF8, G2WWH6, G5ED68, O95248, Q22712, Q54GQ1, Q55E58, Q5F452, Q5FVM6, Q5R6F6, Q5R989, Q63312, Q6NTN5, Q6PDH0, Q6TEL0, Q6ZPE2, Q7SYB5, Q7TPM9, Q80TA6, Q86IV4, Q86UU1, Q86WG5, Q8C2K1, Q8VE11, Q96EF0, Q96QG7, Q9N589, Q9Y216, Q9Y217, Q9Y7Q7, Q9Z2C9, Q9Z2D0, A0JMF6, I1RQE2, Q13615, Q3V1L6

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 59 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
Activation of BAD and translocation to mitochondria	7	118.4×	1e-11
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	104.5×	2e-11
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	104.5×	2e-11
Activation of BH3-only proteins	7	77.2×	1e-10
RHO GTPases activate PKNs	7	49.4×	3e-09
Intrinsic Pathway for Apoptosis	7	45.5×	5e-09
FOXO-mediated transcription	5	37.3×	3e-06
SARS-CoV-1-host interactions	9	35.1×	2e-10

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	32.7×	1e-04
negative regulation of TORC1 signaling	5	28.9×	1e-04
MAPK cascade	6	16.4×	2e-04
intracellular protein localization	8	14.9×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	201
Likely benign	10
Benign	2

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
2664073	NM_001144758.3(PHLDB1):c.2392dup (p.Leu798fs)	Pathogenic
2664074	NM_001144758.3(PHLDB1):c.2690_2693del (p.Leu897fs)	Pathogenic

SpliceAI

4551 predictions. Top by Δscore:

Variant	Effect	Δscore
11:118614542:ACCC:A	acceptor_gain	1.0000
11:118614543:C:G	acceptor_gain	1.0000
11:118614545:C:A	acceptor_gain	1.0000
11:118614548:A:AG	acceptor_gain	1.0000
11:118614549:C:G	acceptor_gain	1.0000
11:118614551:A:AG	acceptor_gain	1.0000
11:118614552:C:G	acceptor_gain	1.0000
11:118614555:ACAG:A	acceptor_loss	1.0000
11:118614556:C:G	acceptor_gain	1.0000
11:118614556:CAGA:C	acceptor_loss	1.0000
11:118614557:A:AC	acceptor_loss	1.0000
11:118614557:A:AG	acceptor_gain	1.0000
11:118614558:G:GT	acceptor_gain	1.0000
11:118614558:GA:G	acceptor_gain	1.0000
11:118614558:GAAA:G	acceptor_gain	1.0000
11:118614678:GGAAG:G	donor_gain	1.0000
11:118614679:GAAGG:G	donor_gain	1.0000
11:118614680:AAGG:A	donor_loss	1.0000
11:118614681:AG:A	donor_gain	1.0000
11:118614681:AGGT:A	donor_loss	1.0000
11:118614682:GG:G	donor_gain	1.0000
11:118614682:GGT:G	donor_loss	1.0000
11:118614683:G:GG	donor_gain	1.0000
11:118614683:GTA:G	donor_loss	1.0000
11:118614684:T:A	donor_loss	1.0000
11:118616038:CAGG:C	acceptor_loss	1.0000
11:118616039:A:AG	acceptor_gain	1.0000
11:118616039:AG:A	acceptor_gain	1.0000
11:118616040:G:GG	acceptor_gain	1.0000
11:118616040:GG:G	acceptor_gain	1.0000

AlphaMissense

8845 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:118650454:G:C	G1261R	1.000
11:118650490:T:A	W1273R	1.000
11:118650490:T:C	W1273R	1.000
11:118650506:T:C	F1278S	1.000
11:118656770:T:A	W1361R	1.000
11:118656770:T:C	W1361R	1.000
11:118656786:T:A	V1366D	1.000
11:118656791:G:A	G1368R	1.000
11:118656791:G:C	G1368R	1.000
11:118656791:G:T	G1368W	1.000
11:118624973:T:C	F132S	0.999
11:118627413:T:C	L197P	0.999
11:118631217:G:C	R613P	0.999
11:118631220:T:C	L614P	0.999
11:118631229:T:A	I617N	0.999
11:118631238:T:C	L620P	0.999
11:118645782:T:C	L1155P	0.999
11:118645790:G:C	A1158P	0.999
11:118650099:T:C	L1226P	0.999
11:118650138:T:A	I1239N	0.999
11:118650448:T:C	C1259R	0.999
11:118650455:G:A	G1261D	0.999
11:118650492:G:C	W1273C	0.999
11:118650492:G:T	W1273C	0.999
11:118650502:T:A	W1277R	0.999
11:118650502:T:C	W1277R	0.999
11:118650505:T:C	F1278L	0.999
11:118650507:T:A	F1278L	0.999
11:118650507:T:G	F1278L	0.999
11:118650512:T:C	F1280S	0.999

dbSNP variants (sampled 300 via entrez): RS1000006153 (11:118642106 G>A), RS1000154796 (11:118619360 C>T), RS1000190209 (11:118638557 G>A), RS1000269510 (11:118657612 T>C), RS1000357203 (11:118650810 A>G), RS1000406875 (11:118644746 A>G), RS1000423354 (11:118619825 T>C), RS1000645013 (11:118624657 A>G), RS1000913858 (11:118610675 G>A), RS1001150711 (11:118651187 A>G), RS1001206643 (11:118606348 G>A,T), RS1001362486 (11:118613253 T>C), RS1001455734 (11:118612815 G>A,T), RS1001566146 (11:118618123 C>A,T), RS1001600783 (11:118639436 G>A)

Disease associations

OMIM: gene MIM:612834 | disease phenotypes: MIM:209900, MIM:620639, MIM:613308

GenCC curated gene-disease

Disease	Classification	Inheritance
osteogenesis imperfecta, type 23	Moderate	Autosomal recessive

Mondo (3): Bardet-Biedl syndrome (MONDO:0015229), osteogenesis imperfecta, type 23 (MONDO:0957988), Diamond-Blackfan anemia 9 (MONDO:0013216)

Orphanet (2): Bardet-Biedl syndrome (Orphanet:110), Diamond-Blackfan anemia (Orphanet:124)

HPO phenotypes

16 total (16 of 16 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000473	Torticollis
HP:0000592	Blue sclerae
HP:0000855	Insulin resistance
HP:0000938	Osteopenia
HP:0000956	Acanthosis nigricans
HP:0001956	Truncal obesity
HP:0002757	Recurrent fractures
HP:0002827	Hip dislocation
HP:0002857	Genu valgum
HP:0002979	Bowing of the legs
HP:0003182	Shallow acetabular fossae
HP:0004322	Short stature
HP:0004349	Reduced bone mineral density
HP:0004565	Severe platyspondyly
HP:0008804	Broad femoral head

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST000439_5	Glioma	1.000000e-08
GCST001058_5	Glioma	5.000000e-11
GCST001670_2	Vitiligo	2.000000e-09
GCST001859_5	Thiazide-induced adverse metabolic effects in hypertensive patients	4.000000e-06
GCST002221_29	Cholesterol, total	1.000000e-08
GCST004235_39	Total cholesterol levels	2.000000e-10
GCST004235_52	Total cholesterol levels	9.000000e-08
GCST004347_13	Glioma	1.000000e-15
GCST004348_8	Non-glioblastoma glioma	6.000000e-43
GCST005931_12	Glioma	8.000000e-06
GCST005933_1	Non-glioblastoma glioma	2.000000e-14
GCST005933_2	Non-glioblastoma glioma	9.000000e-13
GCST006016_22	Serum alkaline phosphatase levels	2.000000e-13
GCST006288_3	Heel bone mineral density	1.000000e-13
GCST006288_381	Heel bone mineral density	4.000000e-09
GCST006614_28	Total cholesterol levels	1.000000e-10
GCST006979_227	Heel bone mineral density	2.000000e-37
GCST007842_2	Glioma	3.000000e-09
GCST008489_5	Celiac disease	2.000000e-08
GCST009597_73	Multiple sclerosis	8.000000e-17
GCST010002_199	Refractive error	3.000000e-34
GCST011001_4	Adult diffuse glioma (IDH mutation, 1p/19q non-codeleted)	2.000000e-09
GCST011004_7	Adult diffuse glioma (IDH mutation)	4.000000e-13
GCST011353_12	Serum alkaline phosphatase levels	4.000000e-14
GCST012442_17	Age-related hearing impairment	1.000000e-14

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004574	total cholesterol measurement
EFO:0004533	alkaline phosphatase measurement
EFO:0009270	heel bone mineral density

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D020788	Bardet-Biedl Syndrome	C10.228.140.617.200; C11.270.684.624; C16.131.077.245.125; C16.320.184.125
C567650	Diamond-Blackfan Anemia 9 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4742300 (PROTEIN-PROTEIN INTERACTION)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	4
bisphenol A	decreases expression	3
sodium arsenite	decreases expression, increases abundance	3
bisphenol S	decreases expression, affects cotreatment, increases methylation	2
Air Pollutants	decreases expression, affects cotreatment, increases abundance, increases expression	2
Estradiol	affects cotreatment, increases expression, decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
pyrimidin-2-one beta-ribofuranoside	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	affects expression, decreases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
coumarin	decreases phosphorylation	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	decreases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
CGP 52608	affects binding, increases reaction	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases 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
CHEMBL4713772	Binding	Protac activity at CRBN/PHLDB1 in human BxPC-3 cells assessed as PHLDB1 degradation incubated for 16 hrs by proteomic analysis	Discovery of a Napabucasin PROTAC as an Effective Degrader of the E3 Ligase ZFP91. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03746522	PHASE3	COMPLETED	Setmelanotide (RM-493), Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alström Syndrome (AS) Participants With Moderate to Severe Obesity
NCT04966741	PHASE3	COMPLETED	Setmelanotide in Pediatric Participants With Rare Genetic Diseases of Obesity
NCT05194124	PHASE3	COMPLETED	Phase 3 Crossover Trial of Two Formulations of Setmelanotide in Participants With Specific Gene Defects in the MC4R Pathway
NCT03490019	PHASE2	WITHDRAWN	Treatment of Bardet-Biedl-Syndrome With Metformin for Evaluation of a Possible Visual Improvement
NCT00078091	Not specified	TERMINATED	Genetics and Clinical Characteristics of Bardet-Biedl Syndrome
NCT00213811	Not specified	COMPLETED	Bardet-Biedl Syndrome Study: Clinical and Genetic Epidemiology Study in Adults
NCT01401998	Not specified	RECRUITING	ARPKD Database Study
NCT02329210	Not specified	RECRUITING	Clinical Registry Investigating Bardet-Biedl Syndrome
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT04461444	Not specified	RECRUITING	COhort for Bardet-Bield Syndrome and Alström Syndrome for Translational Research Monocentric Interventional Study
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT04874909	Not specified	COMPLETED	Classification, Functional Stratification and Biomarkers in Ciliopathy (CILLICORIRCM)
NCT05183802	Not specified	APPROVED_FOR_MARKETING	An Expanded Access Protocol for Setmelanotide for Treatment of Bardet-Biedl Syndrome (BBS)
NCT05400278	Not specified	COMPLETED	Characterizing the Genotype and Phenotype in Adults With Bardet-Biedl Syndrome
NCT06239064	Not specified	ACTIVE_NOT_RECRUITING	Early Genetic Identification of Obesity
NCT06615011	Not specified	NOT_YET_RECRUITING	Bardet Beidle Syndrome in a Syrian Adolescent : a Rare Case Report
NCT07602803	Not specified	COMPLETED	The Effect of GLP1 Agonists on Weight Loss in BBS Cohort in the UK