BCAP31

Summary

BCAP31 (B cell receptor associated protein 31, HGNC:16695) is a protein-coding gene on chromosome Xq28, encoding B-cell receptor-associated protein 31 (P51572). Functions as a chaperone protein. It is a selective cancer dependency (DepMap: 12.0% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the B-cell receptor associated protein 31 superfamily. The encoded protein is a multi-pass transmembrane protein of the endoplasmic reticulum that is involved in the anterograde transport of membrane proteins from the endoplasmic reticulum to the Golgi and in caspase 8-mediated apoptosis. Microdeletions in this gene are associated with contiguous ABCD1/DXS1375E deletion syndrome (CADDS), a neonatal disorder. Alternative splicing of this gene results in multiple transcript variants. Two related pseudogenes have been identified on chromosome 16.

Source: NCBI Gene 10134 — RefSeq curated summary.

At a glance

• Gene–disease (curated): severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome (Definitive, ClinGen)
• Clinical variants (ClinVar): 269 total — 13 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 39
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 12.0% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001256447

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16695
Approved symbol	BCAP31
Name	B cell receptor associated protein 31
Location	Xq28
Locus type	gene with protein product
Status	Approved
Aliases	DXS1357E, BAP31, 6C6-Ag, CDM
Ensembl gene	ENSG00000185825
Ensembl biotype	protein_coding
OMIM	300398
Entrez	10134

Gene structure

Transcript identifiers

Ensembl transcripts: 41 — 37 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000345046, ENST00000416815, ENST00000423827, ENST00000429550, ENST00000430088, ENST00000442093, ENST00000458587, ENST00000468947, ENST00000645006, ENST00000645377, ENST00000645802, ENST00000646514, ENST00000647529, ENST00000672675, ENST00000862066, ENST00000862067, ENST00000862068, ENST00000862069, ENST00000862070, ENST00000862071, ENST00000862072, ENST00000862073, ENST00000862074, ENST00000862075, ENST00000862076, ENST00000862077, ENST00000862078, ENST00000862079, ENST00000862080, ENST00000928871, ENST00000928872, ENST00000928873, ENST00000928874, ENST00000928875, ENST00000968754, ENST00000968755, ENST00000968756, ENST00000968757, ENST00000968758, ENST00000968759, ENST00000968760

RefSeq mRNA: 4 — MANE Select: NM_001256447 NM_001139441, NM_001139457, NM_001256447, NM_005745

CCDS: CCDS14727, CCDS48191

Canonical transcript exons

ENST00000345046 — 8 exons

Exon	Start	End
ENSE00001313039	153702935	153703058
ENSE00001322703	153720872	153720972
ENSE00001325777	153702007	153702107
ENSE00001451907	153700492	153700975
ENSE00001451908	153724334	153724387
ENSE00003485532	153723153	153723288
ENSE00003494963	153703959	153704094
ENSE00003613024	153715542	153715689

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.07.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 50.1270 / max 237.6840, expressed in 1825 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
200901	46.8006	1824
200900	1.8188	957
200899	1.5076	579

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left adrenal gland	UBERON:0001234	99.07	gold quality
right adrenal gland	UBERON:0001233	99.06	gold quality
right adrenal gland cortex	UBERON:0035827	99.03	gold quality
mucosa of transverse colon	UBERON:0004991	99.02	gold quality
left adrenal gland cortex	UBERON:0035825	99.02	gold quality
endometrium epithelium	UBERON:0004811	99.01	gold quality
omental fat pad	UBERON:0010414	98.93	gold quality
peritoneum	UBERON:0002358	98.92	gold quality
adipose tissue of abdominal region	UBERON:0007808	98.92	gold quality
stromal cell of endometrium	CL:0002255	98.87	gold quality
skin of leg	UBERON:0001511	98.84	gold quality
skin of abdomen	UBERON:0001416	98.83	gold quality
Brodmann (1909) area 10	UBERON:0013541	98.80	gold quality
adrenal cortex	UBERON:0001235	98.79	gold quality
islet of Langerhans	UBERON:0000006	98.78	gold quality
adrenal gland	UBERON:0002369	98.75	gold quality
lower esophagus mucosa	UBERON:0035834	98.75	gold quality
right lobe of thyroid gland	UBERON:0001119	98.71	gold quality
esophagus mucosa	UBERON:0002469	98.71	gold quality
adipose tissue	UBERON:0001013	98.70	gold quality
left lobe of thyroid gland	UBERON:0001120	98.69	gold quality
adenohypophysis	UBERON:0002196	98.69	gold quality
body of pancreas	UBERON:0001150	98.67	gold quality
minor salivary gland	UBERON:0001830	98.60	gold quality
cingulate cortex	UBERON:0003027	98.60	gold quality
anterior cingulate cortex	UBERON:0009835	98.60	gold quality
ectocervix	UBERON:0012249	98.60	gold quality
rectum	UBERON:0001052	98.57	gold quality
left uterine tube	UBERON:0001303	98.55	gold quality
endocervix	UBERON:0000458	98.54	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	9.73
E-MTAB-2983	no	1222.71
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

18 targeting BCAP31, 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-6825-5P	99.96	69.81	3431
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-549A-3P	99.54	68.17	825
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-4755-3P	98.77	65.59	1915
HSA-MIR-3138	98.41	67.53	744
HSA-MIR-556-5P	97.75	66.17	473
HSA-MIR-3190-3P	97.61	66.95	1406
HSA-MIR-3616-3P	96.96	65.45	983
HSA-MIR-5192	96.89	63.35	879
HSA-MIR-9900	96.06	65.48	557

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 12.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Contiguous deletion of the X-linked adrenoleukodystrophy gene (ABCD1) and DXS1357E: a novel neonatal phenotype similar to peroxisomal biogenesis disorders. (PMID:11992258)
• CASP8 cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol. (PMID:12668660)
• Data describe a novel human member of the protein tyrosine phosphatase-like B (PTPLB) family, an integral protein of the endoplasmic reticulum membrane, as a BAP31-interacting protein. (PMID:15024066)
• Cleavage of BAP31 leads to the generation of ER- localized, proapoptotic BAP20, which may mediate mitochondrion-ER cross talk through a Ca(2+)-dependent mechanism (PMID:15254227)
• BAP31 may play a role in regulating intracellular trafficking of CD11b/CD18 in neutrophils (PMID:15294914)
• We have characterized a molecular mechanism by which calnexin regulates ER-stress-mediated apoptosis in a manner independent of its chaperone functions but dependent of its binding to Bap31. (PMID:16858427)
• Bap31 performs quality control on class I molecules in two distinct phases: by exporting peptide-loaded class I molecules to the ER/Golgi, and by retrieving class I molecules that have lost peptides in the acidic post-ER environment. (PMID:17056546)
• Bap31 is a component of the endoplasmic reticulum (ER) quality control compartment and that it moves between the peripheral ER and a juxtanuclear ER or ER-related compartment distinct from the conventional ER-Golgi intermediate compartment. (PMID:18287538)
• BAP31 associates with the N terminus of one of its newly synthesized client proteins, the DeltaF508 mutant of CFTR, and promotes its retrotranslocation from the endoplasmic reticulum and degradation by the cytoplasmic 26S proteasome system. (PMID:18555783)
• Results identify B-cell-associated protein 31 as a novel binding partner of the high-risk human papillomavirus 16 E5 proteins and provide insight into how the E5 proteins may modulate the life cycle in differentiating cells. (PMID:18684816)
• Membrane-Associated RING-CH proteins MARCH VIII and MARCH IV associate with Bap31 and target CD81 and CD44 to lysosomes (PMID:21151997)
• Fis1 and Bap31 bridge the mitochondria-ER interface to establish a platform for apoptosis induction. (PMID:21183955)
• BAP31 and BiP are essential for dislocation of SV40 from the endoplasmic reticulum to the cytosol. (PMID:21947079)
• the lack of BAP31 disturbs endoplasmic reticulum (ER) metabolism and impacts the Golgi apparatus, highlighting an important role for BAP31 in ER-to-Golgi crosstalk. (PMID:24011989)
• Hypomethylation in BCAP31 is associated with breast cancer. (PMID:24395279)
• both BCAP31 and ABCD1 were associated with hepatic cholestasis and death before 1 year. Remarkably, a patient with an isolated deletion at the 3’-end of SLC6A8 had a similar severe phenotype as seen in BCAP31 deficiency (PMID:24597975)
• These findings provide, for the first time, mechanistic insights into how BAP31 regulates human embryonic stem cell stemness and survival via control of EpCAM expression. (PMID:24898727)
• Distal Xq28 microdeletions: clarification of the spectrum of contiguous gene deletions involving ABCD1, BCAP31, and SLC6A8 with a new case and review of the literature. (PMID:25044748)
• Transfected human respiratory syncytial virus SH protein co-localizes with transfected BAP31 in cells, and pulls down endogenous BAP31. (PMID:25854864)
• BAP31 expression is an independent prognostic factor for overall survival of patients with postoperative hepatocellular carcinoma (HCC), and low expression levels of BAP31 in HCC may indicate poor outcomes of HCC patient after surgical resection. (PMID:25980696)
• The C-terminal domain of BAP31 is exposed on the cell surface of human embryonic stem cells. (PMID:26102500)
• Data show that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced endoplasmic reticulum (ER) stress was triggered by caspase-8-mediated cleavage of B cell receptor-associated protein 31 (BAP31). (PMID:26212606)
• Data characterized the biochemical properties of plant orthologs of human B-cell receptor-associated protein BAP31 (HsBAP31) termed ‘plant BAP-like proteins’ (PBL proteins). (PMID:27770627)
• This patient’s clinical features, muscle histopathology, brain MRI features, and family history were suggestive of mitochondrial encephalopathy. Whole exome sequencing research study confirmed the diagnosis of BCAP31-associated encephalopathy, DDCH syndrome. (PMID:28332767)
• results suggest that enhanced expression of csBAP31 contributes to poor survival of NSCLC cells (PMID:29145450)
• that BAP31 is a potential prognostic marker for colorectal cancer patients after surgery (PMID:29653744)
• BAP31 regulates cervical cancer cell proliferation by arresting the cell cycle at the G0/G1 stage and that depletion of BAP31 inhibits hyper-proliferation. Depletion of BAP31 inhibits cervical cancer cell invasion and migration by regulating the expression and subcellular localization of Drebrin, M-RIP, SPECC1L, and Nexilin, and then affect the cytoskeleton assemblage. (PMID:30022068)
• BAP31 levels were significantly increased in tumor tissues from patients with gastric intestinal-type adenocarcinoma. Study in gastric cancer cell lines and mouse xenograft model found that BAP31 could combine with p27kip1 and regulate its proteasome degradation. (PMID:30338855)
• essential role for BAP31 in the modulation of tumorigenesis and metastatic potential of cervical cancer (PMID:30503502)
• BAP31 interacts with mitochondria-localized proteins, including Tom40, to stimulate the translocation of NDUFS4, the component of complex I from the cytosol to the mitochondria. (PMID:31206022)
• BCAP31 drives TNBC development by modulating ligand-independent EGFR trafficking and spontaneous EGFR phosphorylation. (PMID:31588230)
• Loss of BAP31 Stimulates Tumor Invasion and Growth. (PMID:31671609)
• BCAP31, a cancer/testis antigen-like protein, can act as a probe for non-small-cell lung cancer metastasis. (PMID:32132574)
• Immunohistochemical expression of BCAP 31 in chronic plaque psoriasis. (PMID:32608336)
• Schimke XLID syndrome results from a deletion in BCAP31. (PMID:32681719)
• Biological roles of the B cell receptor-associated protein 31: Functional Implication in Cancer. (PMID:33439410)
• Further delineation of BCAP31-linked intellectual disability: description of 17 new families with LoF and missense variants. (PMID:33603160)
• BAP31: Physiological functions and roles in disease. (PMID:33930507)
• HNF4A-BAP31-VDAC1 axis synchronously regulates cell proliferation and ferroptosis in gastric cancer. (PMID:37296105)
• BAP31-Mediated miR-206/133b Cluster Promotes Transendothelial Migration and Metastasis of Colorectal Cancer. (PMID:38069061)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	bcap31	ENSDARG00000044972
mus_musculus	Bcap31	ENSMUSG00000002015
rattus_norvegicus	Bcap31	ENSRNOG00000055756
drosophila_melanogaster	CG13887	FBGN0035165
caenorhabditis_elegans		WBGENE00021883

Paralogs (1): BCAP29 (ENSG00000075790)

Protein

Protein identifiers

B-cell receptor-associated protein 31 — P51572 (reviewed: P51572)

Alternative names: 6C6-AG tumor-associated antigen, Protein CDM, p28

All UniProt accessions (7): A0A2R8Y5M6, C9J0M4, C9JM14, C9JMD7, C9JQ75, C9JSP1, P51572

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a chaperone protein. Is one of the most abundant endoplasmic reticulum (ER) proteins. Plays a role in the export of secreted proteins in the ER, the recognition of abnormally folded protein and their targeting to the ER associated-degradation (ERAD). Also serves as a cargo receptor for the export of transmembrane proteins. Plays a role in the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) by stimulating the translocation of NDUFS4 and NDUFB11 from the cytosol to the mitochondria via interaction with TOMM40. In response to ER stress, delocalizes from the ER-mitochondria contact sites and binds BCL2. May be involved in CASP8-mediated apoptosis.

Subunit / interactions. Homodimer and heterodimer with BCAP29. Binds CASP8 (isoform 9) as a complex containing BCAP31, BCAP29, BCL2 and/or BCL2L1. Forms a complex (via C-terminus) with TOMM40 which mediates the translocation of components of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) from the cytosol to the mitochondria; within the complex BCAP31 interacts directly with unprocessed and processed NDUFS4 and NDUFB11. Interacts with VDAC1. Interacts with VAMP3, VAMP1 and membrane IgD immunoglobulins. Interacts with HACD2. Interacts with DNM1L; may form part of a larger protein complex at the endoplasmic reticulum-mitochondrial interface during mitochondrial fission. (Microbial infection) Interacts (via C-terminus) with HRSV membrane protein SH; this interaction is direct.

Subcellular location. Endoplasmic reticulum membrane. Endoplasmic reticulum-Golgi intermediate compartment membrane.

Tissue specificity. Ubiquitous. Highly expressed in neurons and discrete endocrine cells.

Post-translational modifications. Cleaved by CASP8 and other caspases.

Disease relevance. Deafness, dystonia, and cerebral hypomyelination (DDCH) [MIM:300475] An X-linked recessive syndrome characterized by sensorineural deafness, intellectual disability, dysmorphic facial features, dystonia, pyramidal signs, almost no psychomotor development, and hypomyelination on brain imaging. The disease is caused by variants affecting the gene represented in this entry. BCAP31 is deleted in the chromosome Xq28 deletion syndrome which involves BCAP31 and the and the promoter region of ABCD1.

Similarity. Belongs to the BCAP29/BCAP31 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P51572-1	1	yes
P51572-2	2

RefSeq proteins (4): NP_001132913, NP_001132929, NP_001243376, NP_005736 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008417	BAP29/BAP31	Family
IPR040463	BAP29/BAP31_N	Domain
IPR041672	Bap31/Bap29_C	Domain

Pfam: PF05529, PF18035

UniProt features (20 total): topological domain 4, sequence conflict 3, transmembrane region 3, site 2, mutagenesis site 2, initiator methionine 1, chain 1, short sequence motif 1, splice variant 1, helix 1, coiled-coil region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
4JZP	X-RAY DIFFRACTION	2.1
4JZL	X-RAY DIFFRACTION	2.2
8XWX	X-RAY DIFFRACTION	2.69

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51572-F1	84.74	0.51

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): 164–165 (cleavage; by caspase-8); 238–239 (cleavage; by caspase-8)

Mutagenesis-validated functional residues (2):

Position	Phenotype
164	abolishes cleavage by caspases, inhibits apoptotic membrane blebbing and release of cytochrome c from mitochondria; when
238	abolishes cleavage by caspases, inhibits apoptotic membrane blebbing and release of cytochrome c from mitochondria; when

Function

Pathways and Gene Ontology

Reactome pathways

18 pathways

ID	Pathway
R-HSA-111465	Apoptotic cleavage of cellular proteins
R-HSA-75153	Apoptotic execution phase
R-HSA-8980692	RHOA GTPase cycle
R-HSA-983170	Antigen Presentation: Folding, assembly and peptide loading of class I MHC
R-HSA-9833110	RSV-host interactions
R-HSA-109581	Apoptosis
R-HSA-1280218	Adaptive Immune System
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-168256	Immune System
R-HSA-194315	Signaling by Rho GTPases
R-HSA-5357801	Programmed Cell Death
R-HSA-5663205	Infectious disease
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3
R-HSA-9820952	Respiratory Syncytial Virus Infection Pathway
R-HSA-9824446	Viral Infection Pathways
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 0 (showing top):

GO Biological Process (13): obsolete protein targeting to mitochondrion (GO:0006626), intracellular protein transport (GO:0006886), endoplasmic reticulum to Golgi vesicle-mediated transport (GO:0006888), apoptotic process (GO:0006915), spermatogenesis (GO:0007283), response to endoplasmic reticulum stress (GO:0034976), protein localization to endoplasmic reticulum exit site (GO:0070973), positive regulation of retrograde protein transport, ER to cytosol (GO:1904154), positive regulation of ERAD pathway (GO:1904294), positive regulation of ubiquitin-dependent protein catabolic process (GO:2000060), positive regulation of intrinsic apoptotic signaling pathway (GO:2001244), protein transport (GO:0015031), vesicle-mediated transport (GO:0016192)

GO Molecular Function (3): MHC class I protein binding (GO:0042288), protein-containing complex binding (GO:0044877), protein binding (GO:0005515)

GO Cellular Component (13): Golgi membrane (GO:0000139), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), lipid droplet (GO:0005811), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), clathrin-coated vesicle (GO:0030136), Golgi cisterna membrane (GO:0032580), endoplasmic reticulum-Golgi intermediate compartment membrane (GO:0033116), mitochondria-associated endoplasmic reticulum membrane contact site (GO:0044233), perinuclear endoplasmic reticulum (GO:0097038), lumenal side of endoplasmic reticulum membrane (GO:0098553)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Apoptotic execution phase	1
Apoptosis	1
RHO GTPase cycle	1
Class I MHC mediated antigen processing & presentation	1
Respiratory Syncytial Virus Infection Pathway	1
Programmed Cell Death	1
Immune System	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Disease	1
Signaling by Rho GTPases	1
Signal Transduction	1
Viral Infection Pathways	1
Infectious disease	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
cellular anatomical structure	3
intracellular protein localization	2
intracellular transport	2
transport	2
binding	2
bounding membrane of organelle	2
organelle membrane	2
protein transport	1
intercellular transport	1
Golgi vesicle transport	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
developmental process involved in reproduction	1
male gamete generation	1
cellular response to stress	1
protein localization to endoplasmic reticulum	1
retrograde protein transport, ER to cytosol	1
positive regulation of protein exit from endoplasmic reticulum	1
regulation of retrograde protein transport, ER to cytosol	1
ERAD pathway	1
positive regulation of proteasomal protein catabolic process	1
regulation of ERAD pathway	1
positive regulation of response to endoplasmic reticulum stress	1
ubiquitin-dependent protein catabolic process	1
positive regulation of protein catabolic process	1
regulation of ubiquitin-dependent protein catabolic process	1
intrinsic apoptotic signaling pathway	1
positive regulation of intracellular signal transduction	1
positive regulation of apoptotic signaling pathway	1
regulation of intrinsic apoptotic signaling pathway	1
establishment of protein localization	1
cellular process	1
MHC protein binding	1
Golgi apparatus	1
endomembrane system	1
intracellular membrane-bounded organelle	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1

Protein interactions and networks

STRING

2060 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BCAP31	FIS1	Q9Y3D6	995
BCAP31	PACS2	Q86VP3	991
BCAP31	CDIP1	Q9H305	943
BCAP31	CASP8	Q14790	854
BCAP31	CANX	P27824	848
BCAP31	ABCD1	P33897	830
BCAP31	RMDN3	Q96TC7	820
BCAP31	VAPB	O95292	806
BCAP31	PACS1	Q6VY07	769
BCAP31	MFN2	O95140	750
BCAP31	TOMM40	O96008	740
BCAP31	ITPR3	Q14573	738
BCAP31	CFTR	P13569	734
BCAP31	ESR2	Q92731	733
BCAP31	PLXNB3	Q9ULL4	724

IntAct

236 interactions, top by confidence:

A	B	Type	Score
RBM8A	CASC3	psi-mi:“MI:0914”(association)	0.900
ESYT1	ESYT2	psi-mi:“MI:0914”(association)	0.770
UBAC1	UBB	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
BCAP31	BCAP29	psi-mi:“MI:0915”(physical association)	0.670
HTT	BCAP31	psi-mi:“MI:0915”(physical association)	0.670
BCAP29	BCAP31	psi-mi:“MI:0914”(association)	0.670
BCAP31	“SH	psi-mi:“MI:0915”(physical association)	0.640
“SH	BCAP31	psi-mi:“MI:0403”(colocalization)	0.640
“SH	BCAP31	psi-mi:“MI:0915”(physical association)	0.640
“SH	BCAP31	psi-mi:“MI:0407”(direct interaction)	0.640
PARVG	LIMS1	psi-mi:“MI:0914”(association)	0.640
SLC12A2	CLGN	psi-mi:“MI:0914”(association)	0.640
SEC61B	BCAP31	psi-mi:“MI:0915”(physical association)	0.600
TRAM1	BCAP31	psi-mi:“MI:0915”(physical association)	0.600
BCAP31	TRAM1	psi-mi:“MI:0915”(physical association)	0.600
BCAP31	SEC61B	psi-mi:“MI:0915”(physical association)	0.600

BioGRID (789): ITGAM (Co-fractionation), BCAP31 (Co-fractionation), BCAP31 (Two-hybrid), BCAP31 (Affinity Capture-RNA), BCAP31 (Affinity Capture-RNA), BCAP31 (Affinity Capture-RNA), BCAP31 (Co-fractionation), BCAP31 (Co-fractionation), BCAP31 (Co-fractionation), BCAP31 (Co-fractionation), BCAP31 (Co-fractionation), BCAP31 (Co-fractionation), BCAP31 (Co-fractionation), BCAP31 (Co-fractionation), BCAP31 (Co-fractionation)

ESM2 similar proteins: A1DB12, A5JYQ9, B3NIN0, B4IAB8, B4PET6, B4QJ33, B6JWP7, F4JIN3, G5EEK9, G5EGP4, O14290, O74432, O94673, O94689, P35180, P35723, P37296, P46964, P51572, Q02328, Q02774, Q04210, Q07451, Q0WT48, Q18695, Q19555, Q28GF5, Q32KL9, Q4V7N7, Q54E04, Q54K74, Q5B905, Q5R8H3, Q5R9U7, Q61334, Q61335, Q61ZW5, Q641M3, Q6C6U9, Q6FIQ1

Diamond homologs: P51572, Q32KL9, Q5R8H3, Q5R9U7, Q61334, Q61335, Q9UHQ4, Q54K74, Q07451, O14290

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 180 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
COPI-dependent Golgi-to-ER retrograde traffic	9	7.6×	7e-04
COPI-mediated anterograde transport	7	5.9×	1e-02

GO biological processes:

GO term	Partners	Fold	FDR
intra-Golgi vesicle-mediated transport	6	19.3×	2e-04
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	8	16.4×	2e-05
endoplasmic reticulum to Golgi vesicle-mediated transport	12	9.9×	4e-06
ERAD pathway	8	8.8×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	5
Uncertain significance	86
Likely benign	89
Benign	25

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
1339800	NM_001256447.2(BCAP31):c.526A>T (p.Lys176Ter)	Pathogenic
1460375	NC_000023.10:g.(?152980977)(152981164_?)del	Pathogenic
2130100	NM_001256447.2(BCAP31):c.295del (p.Ala99fs)	Pathogenic
280742	NM_001256447.2(BCAP31):c.309_310del (p.Tyr104fs)	Pathogenic
3646779	NM_001256447.2(BCAP31):c.400G>T (p.Glu134Ter)	Pathogenic
374401	NM_001256447.2(BCAP31):c.-44-270C>A	Pathogenic
419708	NM_001256447.2(BCAP31):c.341+2T>G	Pathogenic
488474	NM_001256447.2(BCAP31):c.365_366del (p.Leu122fs)	Pathogenic
620572	NM_001256447.2(BCAP31):c.91A>T (p.Arg31Ter)	Pathogenic
68444	NM_001256447.2(BCAP31):c.194-2A>G	Pathogenic
68445	NC_000023.11:g.153696346_153701690del	Pathogenic
68446	NM_001256447.2(BCAP31):c.97C>T (p.Gln33Ter)	Pathogenic
804102	NM_001256447.2(BCAP31):c.415C>T (p.Gln139Ter)	Pathogenic
1718471	NM_001256447.2(BCAP31):c.67T>C (p.Cys23Arg)	Likely pathogenic
2010989	NM_001256447.2(BCAP31):c.477+1G>C	Likely pathogenic
3338048	NM_001256447.2(BCAP31):c.247C>T (p.Gln83Ter)	Likely pathogenic
4796011	NM_001256447.2(BCAP31):c.466C>T (p.Gln156Ter)	Likely pathogenic
522085	NM_001256447.2(BCAP31):c.739T>C (p.Ter247Gln)	Likely pathogenic

SpliceAI

2050 predictions. Top by Δscore:

Variant	Effect	Δscore
X:153702002:CTGA:C	donor_loss	1.0000
X:153702003:TGA:T	donor_loss	1.0000
X:153702004:GAC:G	donor_loss	1.0000
X:153702005:ACCTG:A	donor_loss	1.0000
X:153702006:CC:C	donor_loss	1.0000
X:153702109:T:C	acceptor_gain	1.0000
X:153702109:T:TC	acceptor_gain	1.0000
X:153702114:A:AC	acceptor_gain	1.0000
X:153702114:A:C	acceptor_gain	1.0000
X:153702117:A:AC	acceptor_gain	1.0000
X:153702117:A:C	acceptor_gain	1.0000
X:153702119:G:GC	acceptor_gain	1.0000
X:153702123:A:AC	acceptor_gain	1.0000
X:153702123:A:C	acceptor_gain	1.0000
X:153702128:C:CT	acceptor_gain	1.0000
X:153702128:C:T	acceptor_gain	1.0000
X:153702129:A:T	acceptor_gain	1.0000
X:153702136:C:CT	acceptor_gain	1.0000
X:153702137:A:T	acceptor_gain	1.0000
X:153702854:TTTGG:T	donor_gain	1.0000
X:153702855:TTGGC:T	donor_gain	1.0000
X:153702901:T:TA	donor_gain	1.0000
X:153702902:C:A	donor_gain	1.0000
X:153702929:CCTCA:C	donor_loss	1.0000
X:153702930:CTCA:C	donor_loss	1.0000
X:153702931:TCA:T	donor_loss	1.0000
X:153702932:CACT:C	donor_loss	1.0000
X:153702933:A:AC	donor_gain	1.0000
X:153702934:C:CA	donor_gain	1.0000
X:153702934:CT:C	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000611187 (X:153714226 T>C), RS1000640480 (X:153713624 A>C), RS1000757056 (X:153721282 G>A), RS1001420913 (X:153717988 T>C), RS1001592745 (X:153724755 C>T), RS1001622413 (X:153724516 G>A,T), RS1002832813 (X:153719761 C>T), RS1003296272 (X:153723031 G>A), RS1003869175 (X:153716632 C>T), RS1003900406 (X:153716472 G>A,T), RS1004078959 (X:153723423 T>C,G), RS1004453665 (X:153723734 C>G,T), RS1004878394 (X:153718392 C>T), RS1004969357 (X:153725221 C>T), RS1005493837 (X:153724775 C>A,T)

Disease associations

OMIM: gene MIM:300398 | disease phenotypes: MIM:300475, MIM:300352

GenCC curated gene-disease

Disease	Classification	Inheritance
severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome	Definitive	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome	Definitive	XL

Mondo (3): severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome (MONDO:0010334), creatine transporter deficiency (MONDO:0010305), microcephaly (MONDO:0001149)

Orphanet (3): Severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome (Orphanet:369939), CADDS (Orphanet:369942), X-linked creatine transporter deficiency (Orphanet:52503)

HPO phenotypes

39 total (30 of 39 shown, HPO-id order):

HPO	Term
HP:0000252	Microcephaly
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000496	Abnormality of eye movement
HP:0000518	Cataract
HP:0000648	Optic atrophy
HP:0000718	Aggressive behavior
HP:0000752	Hyperactivity
HP:0000835	Adrenal hypoplasia
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001332	Dystonia
HP:0001396	Cholestasis
HP:0001419	X-linked recessive inheritance
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001954	Recurrent fever
HP:0001999	Abnormal facial shape
HP:0002059	Cerebral atrophy
HP:0002119	Ventriculomegaly
HP:0002120	Cerebral cortical atrophy
HP:0002445	Tetraplegia
HP:0002500	Abnormal cerebral white matter morphology
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003196	Short nose
HP:0003429	CNS hypomyelination
HP:0003577	Congenital onset

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C564508	Contiguous Abcd1-Dxs1375e Deletion Syndrome (supp.)
C535598	Creatine deficiency, X-linked (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295778 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs17091297	ABCD1, BCAP31		0.00	0

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.16	Kd	69.08	nM	CHEMBL3752910
7.16	ED50	69.08	nM	CHEMBL3752910
5.77	Kd	1703	nM	CHEMBL5653589
5.77	ED50	1703	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 11 total; 2 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-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147940: Binding affinity to human BCAP31 incubated for 45 mins by Kinobead based pull down assay	kd	0.0691	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147940: Binding affinity to human BCAP31 incubated for 45 mins by Kinobead based pull down assay	kd	1.7032	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression	4
Valproic Acid	increases expression, increases methylation	3
sodium arsenite	decreases expression, increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	increases expression, affects cotreatment, affects localization	1
decabromobiphenyl ether	decreases expression	1
tetrabromobisphenol A	decreases expression	1
ochratoxin A	affects cotreatment, decreases expression	1
benzo(e)pyrene	decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine	affects expression, increases reaction	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	increases expression	1
Sunitinib	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Allergens	increases expression	1
Aminoglutethimide	decreases expression	1
Vehicle Emissions	affects expression, increases reaction	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	increases expression	1
Citrinin	affects cotreatment, decreases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118646	Binding	Binding affinity to BCAP31 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2SN	Abcam HEK293T BCAP31 KO	Transformed cell line	Female
CVCL_E1RU	HAP1 BCAP31 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02931682	Not specified	TERMINATED	Observational Study of Males With Creatine Transporter Deficiency
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05642221	Not specified	COMPLETED	Functional Near-Infrared Spectroscopy (fNIRS) Combined With Diffuse Correlation Spectroscopy (DCS) in Neurocognitive Disease as Compared to Healthy Neurotypical Controls
NCT06139172	Not specified	RECRUITING	Web Intervention for Parents of Youth With Genetic Syndromes (WINGS)
NCT06292884	Not specified	UNKNOWN	Optical Imaging as a Tool for Monitoring Brain Function in Creatine Deficiency Syndromes
NCT06868979	Not specified	RECRUITING	Optical Imaging in X-linked Disorders.
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.