BLTP1

Summary

BLTP1 (bridge-like lipid transfer protein family member 1, HGNC:26953) is a protein-coding gene on chromosome 4q27, encoding Bridge-like lipid transfer protein family member 1 (Q2LD37). Bridge-like lipid transfer protein that functions as molecular bridges between endoplasmic reticulum and the membranes targeted for lipid delivery.

This gene is located on the long arm of chromosome 4 in a region that is associated with susceptibility to celiac disease. The encoded protein is similar to a Chinese hamster protein that is associated with spermatocyte and adipocyte differentiation. The C-terminus of the protein is also similar to a Caenorhabditis elegans protein that plays a role in lipid storage. In mammals, this protein is thought to function in the regulation of epithelial growth and differentiation, and in tumor development.

Source: NCBI Gene 84162 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Alkuraya-Kucinskas syndrome (Definitive, ClinGen)
• GWAS associations: 41
• Clinical variants (ClinVar): 870 total — 24 pathogenic, 30 likely-pathogenic
• Phenotypes (HPO): 52
• MANE Select transcript: NM_001384125

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26953
Approved symbol	BLTP1
Name	bridge-like lipid transfer protein family member 1
Location	4q27
Locus type	gene with protein product
Status	Approved
Aliases	FLJ21404, FSA, KIAA1371, Tweek
Ensembl gene	ENSG00000138688
Ensembl biotype	protein_coding
OMIM	611565
Entrez	84162

Gene structure

Transcript identifiers

Ensembl transcripts: 42 — 24 retained_intron, 11 protein_coding, 4 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000264501, ENST00000306802, ENST00000388738, ENST00000419325, ENST00000421930, ENST00000424425, ENST00000438707, ENST00000442707, ENST00000446180, ENST00000449251, ENST00000470182, ENST00000480651, ENST00000482114, ENST00000483357, ENST00000491933, ENST00000495260, ENST00000679879, ENST00000684873, ENST00000684987, ENST00000685587, ENST00000685604, ENST00000686040, ENST00000686075, ENST00000686093, ENST00000686836, ENST00000686950, ENST00000687387, ENST00000687476, ENST00000688248, ENST00000688322, ENST00000688368, ENST00000688823, ENST00000688874, ENST00000688884, ENST00000689316, ENST00000690050, ENST00000690272, ENST00000690536, ENST00000691302, ENST00000693334, ENST00000693357, ENST00000693420

RefSeq mRNA: 2 — MANE Select: NM_001384125 NM_001384125, NM_015312

CCDS: CCDS43267, CCDS93617

Canonical transcript exons

ENST00000679879 — 88 exons

Exon	Start	End
ENSE00000447359	122316732	122316862
ENSE00000738330	122301300	122301397
ENSE00000738342	122304798	122304983
ENSE00000738346	122305877	122306045
ENSE00000738350	122307949	122308160
ENSE00000842039	122313628	122313687
ENSE00000842042	122318147	122318270
ENSE00000842043	122324427	122324536
ENSE00000935282	122356621	122356755
ENSE00000935287	122359557	122359722
ENSE00000935298	122309266	122309464
ENSE00000935302	122315462	122315688
ENSE00001160372	122266783	122266958
ENSE00001160378	122264252	122264427
ENSE00001160388	122263442	122263600
ENSE00001176807	122271018	122271724
ENSE00001176813	122262764	122262983
ENSE00001176843	122224498	122224677
ENSE00001176851	122209159	122209337
ENSE00001203827	122258701	122258843
ENSE00001203833	122257255	122257495
ENSE00001203840	122255131	122255283
ENSE00001239044	122289087	122289192
ENSE00001239050	122286541	122286785
ENSE00001239054	122281536	122281774
ENSE00001239059	122279775	122279981
ENSE00001239066	122275972	122276022
ENSE00001239070	122274343	122274436
ENSE00001239079	122272160	122272405
ENSE00001379983	122187895	122188088
ENSE00001382219	122186036	122186222
ENSE00001383307	122239516	122240353
ENSE00001385384	122187431	122187512
ENSE00001418068	122196635	122196791
ENSE00001431745	122190000	122190079
ENSE00001433012	122192229	122192379
ENSE00001481895	122325855	122325917
ENSE00001503815	122362031	122362752
ENSE00001503816	122334344	122334545
ENSE00001503817	122254805	122254955
ENSE00001503819	122254195	122254346
ENSE00001535991	122170615	122170744
ENSE00001535994	122154025	122154112
ENSE00001536200	122250362	122250573
ENSE00001536203	122249485	122249682
ENSE00001536205	122247158	122247357
ENSE00001536208	122246152	122246298
ENSE00001536210	122245020	122245140
ENSE00001536211	122243854	122244027
ENSE00001536213	122242998	122243068
ENSE00001536293	122175850	122175914
ENSE00001536296	122174574	122174652
ENSE00001536298	122173036	122173152
ENSE00001594461	122353814	122354017
ENSE00001602802	122336881	122337020
ENSE00001607831	122328104	122328357
ENSE00001615144	122352904	122353155
ENSE00001655781	122336192	122336353
ENSE00001667939	122348567	122348717
ENSE00001729503	122316348	122316548
ENSE00001738142	122349857	122350074
ENSE00001742292	122349158	122349315
ENSE00001744411	122339207	122339408
ENSE00001768550	122355796	122355990
ENSE00001800557	122325230	122325320
ENSE00002460599	122346623	122346760
ENSE00002462936	122344382	122344561
ENSE00002473012	122347522	122347779
ENSE00002530372	122343410	122343610
ENSE00003459601	122349450	122349642
ENSE00003461516	122234773	122235023
ENSE00003469912	122197196	122197274
ENSE00003472897	122229121	122229240
ENSE00003506524	122219340	122219567
ENSE00003524853	122210887	122211095
ENSE00003526904	122199359	122199450
ENSE00003538381	122333629	122333809
ENSE00003568208	122226707	122226835
ENSE00003574187	122207541	122207638
ENSE00003577481	122246683	122246810
ENSE00003602736	122201009	122201126
ENSE00003621910	122331326	122331541
ENSE00003650020	122220333	122220470
ENSE00003654888	122229931	122230211
ENSE00003671868	122207110	122207265
ENSE00003675765	122238092	122238350
ENSE00003676640	122209818	122209924
ENSE00003912961	122152331	122152584

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 98.06.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.4487 / max 342.0718, expressed in 1793 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
49523	26.4073	1790
49524	0.6155	279
49526	0.2529	97
49525	0.1559	94
203328	0.0171	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	98.06	gold quality
corpus callosum	UBERON:0002336	97.72	gold quality
postcentral gyrus	UBERON:0002581	97.58	gold quality
calcaneal tendon	UBERON:0003701	97.52	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.18	gold quality
biceps brachii	UBERON:0001507	97.10	gold quality
skin of hip	UBERON:0001554	97.08	gold quality
parietal lobe	UBERON:0001872	97.08	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.07	gold quality
jejunal mucosa	UBERON:0000399	96.96	gold quality
blood vessel layer	UBERON:0004797	96.92	gold quality
cerebellar vermis	UBERON:0004720	96.90	gold quality
primary visual cortex	UBERON:0002436	96.86	gold quality
caput epididymis	UBERON:0004358	96.83	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.76	gold quality
choroid plexus epithelium	UBERON:0003911	96.72	gold quality
subthalamic nucleus	UBERON:0001906	96.57	gold quality
seminal vesicle	UBERON:0000998	96.52	gold quality
diaphragm	UBERON:0001103	96.52	gold quality
occipital lobe	UBERON:0002021	96.37	gold quality
cauda epididymis	UBERON:0004360	96.37	gold quality
Brodmann (1909) area 10	UBERON:0013541	96.34	gold quality
pigmented layer of retina	UBERON:0001782	96.27	gold quality
retina	UBERON:0000966	96.25	gold quality
superior frontal gyrus	UBERON:0002661	96.18	gold quality
superior vestibular nucleus	UBERON:0007227	96.15	gold quality
jejunum	UBERON:0002115	96.12	gold quality
corpus epididymis	UBERON:0004359	96.12	gold quality
middle frontal gyrus	UBERON:0002702	96.11	gold quality
frontal pole	UBERON:0002795	96.05	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-100618	no	522.11
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 10)

• Genetic variation in a linkage disequilibrium block encompassing the KIAA1109-TENR-IL2-IL21 genes predisposes to celiac disease. (PMID:17558408)
• Using a family-based study we have provided a trend for the association of the KIAA1109/Tenr/IL2/IL21 gene region with rheumatoid arthritis in populations of European descent. (PMID:19302705)
• The KIAA1109-TENR-IL2-IL21 gene cluster, that encodes an interleukin (IL-21) that plays an important role in Th17 cell biology, is the 20th locus for which there is a genome-wide level of support for association with rheumatoid arthritis. (PMID:20553587)
• KIAA1109-rs4505848 polymorphism might be associated with the development of Behcet’s disease. (PMID:22876110)
• Polymorphisms from the KIAA1109-interleukin 2 (IL2)-IL21 block in the 4q27 chromosome may contribute to the genetic susceptibility of ADs in the Tunisian population. (PMID:25037274)
• Whole-exome and targeted sequencing of 13 individuals from 10 unrelated families with overlapping clinical manifestations identified loss-of-function and missense variants in KIAA1109 allowing delineation of an autosomal-recessive multi-system syndrome. (PMID:29290337)
• KIAA1109 has an association with susceptibility to the development of moderate-to-severe asthma. (PMID:30552067)
• Prenatal cerebral imaging features of a new syndromic entity related to KIAA1109 pathogenic variants mimicking tubulinopathy. (PMID:31736083)
• KIAA1109 gene mutation in surviving patients with Alkuraya-Kucinskas syndrome: a review of literature. (PMID:32590954)
• Two novel pathogenic variants in KIAA1109 causing Alkuraya-Kucinskas syndrome in two Czech Roma brothers. (PMID:32657846)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	kiaa1109	ENSDARG00000062330
mus_musculus	Bltp1	ENSMUSG00000037270
rattus_norvegicus	Bltp1	ENSRNOG00000038436
drosophila_melanogaster	tweek	FBGN0261671
caenorhabditis_elegans	lpd-3	WBGENE00003060

Protein

Protein identifiers

Bridge-like lipid transfer protein family member 1 — Q2LD37 (reviewed: Q2LD37)

Alternative names: Fragile site-associated protein

All UniProt accessions (15): A0A7P0T938, A0A8I5KQV3, A0A8I5KRW6, A0A8I5KWC0, A0A8I5KWM3, A0A8J8Z0T9, Q2LD37, H0Y781, H3BLT5, H7C070, H7C0G8, H7C0Y8, H7C121, H7C2X5, H7C3N8

UniProt curated annotations — full annotation on UniProt →

Function. Bridge-like lipid transfer protein that functions as molecular bridges between endoplasmic reticulum and the membranes targeted for lipid delivery. Forms a tunnel with multiple beta-grooves that allows the transport of phospholipids. Provides phosphatidylethanolamine for glycosylphosphatidylinositol (GPI) anchor synthesis in the endoplasmic reticulum. Plays a role in endosomal trafficking and endosome recycling. Also involved in the actin cytoskeleton and cilia structural dynamics. Acts as a regulator of phagocytosis. Required for the formation of endoplasmic reticulum-plasma membrane junctions which are critical for lipid exchange.

Subunit / interactions. Interacts (via the N-terminus) with LTAP1; the interaction is direct.

Subcellular location. Endoplasmic reticulum membrane. Apical cell membrane. Cell membrane. Mitochondrion membrane.

Tissue specificity. Highly expressed in testis and ovary. Weakly or not expressed in other tissues.

Disease relevance. Alkuraya-Kucinskas syndrome (ALKKUCS) [MIM:617822] An autosomal recessive syndrome characterized by brain atrophy and arthrogryposis. Patients present with cerebral parenchymal underdevelopment, lissencephaly, severe to mild ventriculomegaly, and cerebellar hypoplasia with brainstem dysgenesis. Most affected individuals die in utero or soon after birth. The few patients who survive have variable intellectual disability and may have seizures. Facial dysmorphism, cardiac and ophthalmologic anomalies, such as microphthalmia and cataract, are additional features. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. KIAA1109 is mapped in the genomic region associated with susceptibility to celiac disease (CELIAC6).

Similarity. Belongs to the bridge-like lipid transfer protein family member 1 family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q2LD37-1	1	yes
Q2LD37-2	2
Q2LD37-4	4
Q2LD37-5	5
Q2LD37-6	6
Q2LD37-7	7

RefSeq proteins (2): NP_001371054, NP_056127 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR033616	BLTP1	Family
IPR047104	BLTP1_N	Domain
IPR056741	BLTP1_M	Domain
IPR056742	BLTP1_C	Domain

Pfam: PF20413, PF25039, PF25040

UniProt features (92 total): compositionally biased region 23, sequence variant 18, region of interest 17, modified residue 14, splice variant 9, sequence conflict 7, topological domain 2, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for Q2LD37 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

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 (14): 1301, 1305, 1323, 1325, 1355, 1406, 1805, 1808, 2601, 2603, 2755, 3562, 3653, 4124

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 284 (showing top): CLAUS_PGR_POSITIVE_MENINGIOMA_UP, GCM_MAP4K4, GOBP_EPITHELIUM_DEVELOPMENT, GCM_PTPRD, GOBP_GROWTH, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_SYNAPTIC_VESICLE_RECYCLING, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT, GOBP_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, FOSTER_TOLERANT_MACROPHAGE_UP, DACOSTA_UV_RESPONSE_VIA_ERCC3_COMMON_DN, GOCC_MITOCHONDRIAL_ENVELOPE, HELLER_HDAC_TARGETS_SILENCED_BY_METHYLATION_UP, GOBP_ENDOCYTIC_RECYCLING, FLECHNER_BIOPSY_KIDNEY_TRANSPLANT_REJECTED_VS_OK_DN

GO Biological Process (10): regulation of cell growth (GO:0001558), phagocytosis (GO:0006909), endosomal transport (GO:0016197), regulation of epithelial cell differentiation (GO:0030856), endocytic recycling (GO:0032456), synaptic vesicle endocytosis (GO:0048488), intermembrane lipid transfer (GO:0120009), lipid transport (GO:0006869), response to cold (GO:0009409), phospholipid transport (GO:0015914)

GO Molecular Function (2): phosphatidylethanolamine transfer activity (GO:1904121), protein binding (GO:0005515)

GO Cellular Component (9): nucleus (GO:0005634), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), membrane (GO:0016020), mitochondrial membrane (GO:0031966), presynapse (GO:0098793), endoplasmic reticulum-plasma membrane contact site (GO:0140268), mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	3
lipid transport	2
organelle membrane	2
cellular anatomical structure	2
cytoplasm	2
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
endocytosis	1
vesicle-mediated transport	1
intracellular transport	1
epithelial cell differentiation	1
regulation of cell differentiation	1
regulation of multicellular organismal development	1
endosomal transport	1
vesicle-mediated transport to the plasma membrane	1
synaptic vesicle recycling	1
presynaptic endocytosis	1
membrane organization	1
transport	1
lipid localization	1
response to stress	1
response to temperature stimulus	1
organophosphate ester transport	1
phospholipid transfer activity	1
binding	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
mitochondrion	1
mitochondrial envelope	1
synapse	1
organelle membrane contact site	1
endomembrane system	1

Protein interactions and networks

STRING

984 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BLTP1	ADAD1	Q96M93	959
BLTP1	TAGAP	Q8N103	733
BLTP1	SH2B3	Q9UQQ2	691
BLTP1	MYO9B	Q13459	649
BLTP1	RGS1	Q08116	618
BLTP1	IL2	P01585	596
BLTP1	TOR1A	O14656	591
BLTP1	IL18R1	Q13478	582
BLTP1	ZMIZ2	Q8NF64	559
BLTP1	ARHGEF19	Q8IW93	542
BLTP1	ALS2CL	Q60I27	529
BLTP1	CTNNB1	P35222	484
BLTP1	LACRT	Q9GZZ8	469
BLTP1	Q5Y7H0	Q5Y7H0	464
BLTP1	BAG2	O95816	459

IntAct

14 interactions, top by confidence:

A	B	Type	Score
KDM5A	SIN3B	psi-mi:“MI:0914”(association)	0.640
BLTP1	SOD1	psi-mi:“MI:0915”(physical association)	0.400
S100A9	BLTP1	psi-mi:“MI:0915”(physical association)	0.370
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
CCDC28A	BLTP1	psi-mi:“MI:0914”(association)	0.350
C1orf43	ADCY3	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
SLC27A6	NBAS	psi-mi:“MI:0914”(association)	0.350
FMR1	BLTP1	psi-mi:“MI:0915”(physical association)	0.000
CTNNB1	BLTP1	psi-mi:“MI:0915”(physical association)	0.000
BLTP1	SMAD2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (51): KIAA1109 (Affinity Capture-MS), KIAA1109 (Affinity Capture-MS), KIAA1109 (Affinity Capture-RNA), KIAA1109 (Affinity Capture-RNA), KIAA1109 (Proximity Label-MS), KIAA1109 (Proximity Label-MS), KIAA1109 (Proximity Label-MS), KIAA1109 (Affinity Capture-RNA), KIAA1109 (Proximity Label-MS), KIAA1109 (Affinity Capture-MS), KIAA1109 (Proximity Label-MS), KIAA1109 (Affinity Capture-MS), KIAA1109 (Affinity Capture-MS), KIAA1109 (Affinity Capture-MS), KIAA1109 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IES7, A0JN62, A0JNW5, A2AAE1, A2AGL3, A2RSJ4, A2RT67, A2RUS2, A2RV80, B0LPN4, B1H2P5, E7F240, E9Q401, O00507, O94967, P30957, P48553, P51593, Q14161, Q2LD37, Q3TLI0, Q3UHE1, Q3UVG3, Q3UX43, Q5F361, Q5M7Q1, Q5RAQ5, Q5ZJK1, Q658Y4, Q68CL5, Q6BDS2, Q6P6Y1, Q6TEP1, Q6VNB8, Q7TMY8, Q7TSG1, Q7Z6Z7, Q8BHY8, Q8CB44, Q8CGF6

Diamond homologs: A0A0R4IES7, A2AAE1, Q2LD37

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	30
Uncertain significance	538
Likely benign	73
Benign	117

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1030489	NM_001384125.1(BLTP1):c.3263del (p.His1088fs)	Pathogenic
1252048	NM_001384125.1(BLTP1):c.12331G>T (p.Glu4111Ter)	Pathogenic
1252049	NM_001384125.1(BLTP1):c.11514-1G>A	Pathogenic
1323143	NM_001384125.1(BLTP1):c.9370_9371dup (p.Val3124_Ile3125insTer)	Pathogenic
1323144	NM_001384125.1(BLTP1):c.4287dup (p.Arg1430Ter)	Pathogenic
183349	NM_001384125.1(BLTP1):c.1557T>A (p.Tyr519Ter)	Pathogenic
2134895	NM_001384125.1(BLTP1):c.247del (p.Val83fs)	Pathogenic
2576960	NM_001384125.1(BLTP1):c.12997G>A (p.Ala4333Thr)	Pathogenic
2581689	NM_001384125.1(BLTP1):c.8740C>T (p.Arg2914Ter)	Pathogenic
280219	NM_001384125.1(BLTP1):c.997dup (p.Ile333fs)	Pathogenic
3063996	NM_001384125.1(BLTP1):c.3925C>T (p.Arg1309Ter)	Pathogenic
4072343	NM_001384125.1(BLTP1):c.11047C>T (p.Arg3683Ter)	Pathogenic
451550	NM_001384125.1(BLTP1):c.13387C>T (p.Arg4463Ter)	Pathogenic
4535598	NM_001384125.1(BLTP1):c.12546_12547del (p.Glu4182fs)	Pathogenic
4813753	NM_001384125.1(BLTP1):c.13408del (p.Thr4470fs)	Pathogenic
4813754	NM_001384125.1(BLTP1):c.14805_14806insAA (p.Glu4936fs)	Pathogenic
4847798	NM_001384125.1(BLTP1):c.1756del (p.Glu586fs)	Pathogenic
487548	NM_001384125.1(BLTP1):c.5599G>A (p.Val1867Met)	Pathogenic
487549	NM_001384125.1(BLTP1):c.3611del (p.Asn1204fs)	Pathogenic
487551	NM_001384125.1(BLTP1):c.10153G>C (p.Gly3385Arg)	Pathogenic
938790	NM_001384125.1(BLTP1):c.12914_12915insCCTG (p.Ser4306fs)	Pathogenic
978641	NM_001384125.1(BLTP1):c.9153del (p.Val3052fs)	Pathogenic
987175	NM_001384125.1(BLTP1):c.5494_5497del (p.Arg1832fs)	Pathogenic
987176	NM_001384125.1(BLTP1):c.5499del (p.Asp1835fs)	Pathogenic
1205698	NM_001384125.1(BLTP1):c.7096C>T (p.Gln2366Ter)	Likely pathogenic
1324618	NM_001384125.1(BLTP1):c.11413C>T (p.Arg3805Ter)	Likely pathogenic
1705258	NM_001384125.1(BLTP1):c.12617-2A>G	Likely pathogenic
2440988	NM_001384125.1(BLTP1):c.772C>T (p.Arg258Ter)	Likely pathogenic
2440990	NM_001384125.1(BLTP1):c.10872-1G>C	Likely pathogenic
2440993	NM_001384125.1(BLTP1):c.4916+2T>C	Likely pathogenic

SpliceAI

14321 predictions. Top by Δscore:

Variant	Effect	Δscore
4:122154109:TTGGG:T	donor_loss	1.0000
4:122154110:TGGGT:T	donor_loss	1.0000
4:122154111:GG:G	donor_gain	1.0000
4:122154112:GG:G	donor_gain	1.0000
4:122154112:GGT:G	donor_loss	1.0000
4:122154113:G:GG	donor_gain	1.0000
4:122154113:GTA:G	donor_loss	1.0000
4:122154114:T:A	donor_loss	1.0000
4:122159768:G:GT	donor_gain	1.0000
4:122159781:G:T	donor_gain	1.0000
4:122159811:TTTTA:T	donor_gain	1.0000
4:122175845:CTTAG:C	acceptor_loss	1.0000
4:122175846:TTAG:T	acceptor_loss	1.0000
4:122175848:A:AG	acceptor_gain	1.0000
4:122175848:AG:A	acceptor_gain	1.0000
4:122175849:G:A	acceptor_gain	1.0000
4:122175849:G:GA	acceptor_gain	1.0000
4:122175849:GGA:G	acceptor_gain	1.0000
4:122175849:GGATT:G	acceptor_gain	1.0000
4:122175910:ACATG:A	donor_gain	1.0000
4:122175911:CATG:C	donor_gain	1.0000
4:122175912:ATG:A	donor_gain	1.0000
4:122175912:ATGGT:A	donor_loss	1.0000
4:122175913:TG:T	donor_gain	1.0000
4:122175914:GG:G	donor_gain	1.0000
4:122175915:G:GA	donor_loss	1.0000
4:122175915:G:GG	donor_gain	1.0000
4:122175916:T:A	donor_loss	1.0000
4:122186021:A:AG	acceptor_gain	1.0000
4:122186021:AATT:A	acceptor_gain	1.0000

AlphaMissense

33508 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:122173056:T:A	W40R	1.000
4:122173056:T:C	W40R	1.000
4:122175881:T:A	W109R	1.000
4:122175881:T:C	W109R	1.000
4:122175883:G:C	W109C	1.000
4:122175883:G:T	W109C	1.000
4:122190005:C:A	P276Q	1.000
4:122190008:G:C	R277T	1.000
4:122190009:A:C	R277S	1.000
4:122190009:A:T	R277S	1.000
4:122190016:G:A	G280R	1.000
4:122190016:G:C	G280R	1.000
4:122190022:G:C	G282R	1.000
4:122190025:T:C	F283L	1.000
4:122190027:T:A	F283L	1.000
4:122190027:T:G	F283L	1.000
4:122190070:G:C	D298H	1.000
4:122192357:G:A	G344R	1.000
4:122192357:G:C	G344R	1.000
4:122192358:G:A	G344E	1.000
4:122192363:T:A	W346R	1.000
4:122192363:T:C	W346R	1.000
4:122192365:G:C	W346C	1.000
4:122192365:G:T	W346C	1.000
4:122196715:G:C	R378T	1.000
4:122199379:G:A	G437R	1.000
4:122199379:G:C	G437R	1.000
4:122254848:T:A	W2040R	1.000
4:122254848:T:C	W2040R	1.000
4:122257291:G:C	G2139R	1.000

dbSNP variants (sampled 300 via entrez): RS1000016384 (4:122288949 T>G), RS1000029152 (4:122235165 G>A), RS1000034864 (4:122340564 G>A), RS1000039830 (4:122314894 A>G), RS1000044511 (4:122171849 C>G,T), RS1000071363 (4:122240696 T>G), RS1000072980 (4:122165649 C>G), RS1000073765 (4:122348019 G>C), RS10000810 (4:122222496 G>T), RS1000133230 (4:122239746 C>A,T), RS1000133504 (4:122193868 T>C), RS1000149138 (4:122257666 C>A), RS1000152157 (4:122200059 C>G), RS1000182473 (4:122246827 T>G), RS1000183598 (4:122200353 G>A)

Disease associations

OMIM: gene MIM:611565 | disease phenotypes: MIM:617822, MIM:119800, MIM:220200, MIM:617468, MIM:208150, MIM:191830

GenCC curated gene-disease

Disease	Classification	Inheritance
Alkuraya-Kucinskas syndrome	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Alkuraya-Kucinskas syndrome	Definitive	AR

Mondo (8): Alkuraya-Kucinskas syndrome (MONDO:0060631), hydrocephalus (MONDO:0001150), clubfoot (MONDO:0007342), Dandy-Walker syndrome (MONDO:0009072), arthrogryposis multiplex congenita (MONDO:0015168), fetal akinesia deformation sequence 1 (MONDO:0100101), renal agenesis (MONDO:0018470), right aortic arch (MONDO:0020417)

Orphanet (7): KIAA1109-related early lethal congenital brain malformations-arthrogryposis syndrome (Orphanet:610569), Familial clubfoot with or without associated lower limb anomalies (Orphanet:199315), Isolated Dandy-Walker malformation (Orphanet:217), Arthrogryposis multiplex congenita (Orphanet:1037), Fetal akinesia deformation sequence (Orphanet:994), Renal agenesis (Orphanet:411709), Right aortic arch (Orphanet:99081)

HPO phenotypes

52 total (30 of 52 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000046	Small scrotum
HP:0000054	Micropenis
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000256	Macrocephaly
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000463	Anteverted nares
HP:0000465	Webbed neck
HP:0000476	Cystic hygroma
HP:0000486	Strabismus
HP:0000496	Abnormality of eye movement
HP:0000518	Cataract
HP:0000540	Hypermetropia
HP:0000582	Upslanted palpebral fissure
HP:0000601	Hypotelorism
HP:0000657	Oculomotor apraxia
HP:0000708	Atypical behavior
HP:0000969	Edema
HP:0001181	Adducted thumb
HP:0001188	Hand clenching
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001305	Dandy-Walker malformation
HP:0001321	Cerebellar hypoplasia

GWAS associations

41 associations (top):

Study	Trait	p-value
GCST000048_2	Celiac disease	1.000000e-14
GCST000157_8	Celiac disease	3.000000e-13
GCST002084_6	Allergic sensitization	6.000000e-10
GCST002520_7	Celiac disease	3.000000e-11
GCST002740_32	Inflammatory skin disease	1.000000e-06
GCST004131_73	Inflammatory bowel disease	1.000000e-07
GCST004132_89	Crohn’s disease	9.000000e-07
GCST004599_93	Mean platelet volume	8.000000e-10
GCST004644_1	Vaso-occlusive pain in sickle-cell anemia	6.000000e-08
GCST004861_51	Itch intensity from mosquito bite	3.000000e-09
GCST004861_52	Itch intensity from mosquito bite	4.000000e-09
GCST004863_134	Mosquito bite size	3.000000e-07
GCST004866_24	Alopecia areata	1.000000e-06
GCST005523_20	Celiac disease	2.000000e-38
GCST005790_94	Rosacea symptom severity	4.000000e-06
GCST006911_14	Asthma (moderate or severe)	3.000000e-09
GCST006943_36	Feeling miserable	1.000000e-08
GCST006947_50	Feeling fed-up	2.000000e-08
GCST007563_21	Allergic disease (asthma, hay fever or eczema)	4.000000e-10
GCST007564_10	Asthma or allergic disease (pleiotropy)	3.000000e-12
GCST007798_65	Asthma	6.000000e-19
GCST008103_153	Bipolar disorder	5.000000e-06
GCST008489_17	Celiac disease	1.000000e-08
GCST008489_18	Celiac disease	1.000000e-08
GCST008644_4	Celiac disease and Rheumatoid arthritis	6.000000e-09
GCST008916_105	Asthma	1.000000e-12
GCST008916_118	Asthma	4.000000e-15
GCST008916_22	Asthma	2.000000e-08
GCST009524_291	Household income (MTAG)	5.000000e-09
GCST009798_57	Asthma	8.000000e-12

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0005298	allergic sensitization measurement
EFO:0008316	vaso-occlusive pain measurement
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0009180	rosacea severity measurement
EFO:0009598	feeling miserable measurement
EFO:0009588	feeling “fed-up” measurement
EFO:0009695	household income
EFO:0004847	age at onset
EFO:0007991	eosinophil percentage of leukocytes
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D003025	Clubfoot	C05.330.488.655.063; C05.330.495.681.063; C05.660.585.512.380.813.063; C16.131.621.585.512.500.681.063
D003616	Dandy-Walker Syndrome	C10.228.140.252.300; C10.228.140.602.500; C10.500.205; C16.131.666.205
D006849	Hydrocephalus	C10.228.140.602

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
potassium chromate(VI)	affects cotreatment, decreases expression	2
chromium hexavalent ion	decreases expression, increases abundance, increases expression	2
perfluorooctane sulfonic acid	increases expression, decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
FR900359	affects phosphorylation	1
alpha-pinene	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
bisphenol A	increases expression	1
trichostatin A	affects expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	decreases expression, increases abundance	1
zinc chromate	increases abundance, increases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression, increases expression	1
tamibarotene	affects expression	1
abrine	decreases expression	1
jinfukang	decreases expression	1
(+)-JQ1 compound	increases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Acrolein	increases oxidation, increases abundance, affects cotreatment, decreases expression	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Benztropine	affects cotreatment, decreases expression	1
Cadmium	increases abundance, increases expression	1
Caffeine	affects phosphorylation	1
Cuprizone	decreases expression, affects cotreatment	1
Ozone	increases abundance, affects cotreatment, decreases expression, increases oxidation	1
Quercetin	increases phosphorylation	1
Tretinoin	decreases expression	1
Valproic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01323764	PHASE4	COMPLETED	ShuntCheck Versus Radionuclide in Evaluating Shunt Function in Symptomatic NPH Patients
NCT01685450	PHASE4	UNKNOWN	NIMIP: Non Invasive Measurement of the Intracranial Pressure
NCT03513757	PHASE4	COMPLETED	Dexmedetomidine and Propofol for Pediatric MRI Sedation
NCT07547826	PHASE4	NOT_YET_RECRUITING	Efficacy and Cost-Effectiveness of Topical Vancomycin Powder in Preventing Pediatric Ventriculoperitoneal Shunt Infections Across Different Etiologies
NCT04564430	PHASE4	UNKNOWN	Clonidine for Tourniquet-related Pain in Children
NCT04766684	PHASE4	COMPLETED	Clubfoot Tenotomy Trial
NCT00196196	PHASE3	COMPLETED	A Precision and Accuracy Study of the Codman Valve Position Verification (VPV) System.
NCT00286104	PHASE3	COMPLETED	Impact of Ventricular Catheter Used With Antimicrobial Agents on Patients With a Ventricular Catheter
NCT01936272	PHASE3	ACTIVE_NOT_RECRUITING	Randomized Controlled Trial of Shunt vs ETV/CPC for PIH in Ugandan Infants
NCT02425761	PHASE3	UNKNOWN	The CSF Shunt Entry Site Trial
NCT02512809	PHASE3	TERMINATED	Isoflurane-induced Neuroinflammation in Children With Hydrocephalus
NCT04177914	PHASE3	RECRUITING	HCRN Endoscopic Versus Shunt Treatment of Hydrocephalus in Infants
NCT00652470	PHASE2	COMPLETED	A Study Comparing Two Treatments for Infants With Hydrocephalus
NCT05001750	PHASE1	RECRUITING	Prophylactic Antibiotics Useful With Antibiotic Impregnated External Ventricular Drains (EVDs)?
NCT01878136	PHASE1/PHASE2	WITHDRAWN	Effect of Intraventricular tPA Following Aneurysmal Subarachnoid Hemorrhage
NCT05476874	PHASE1/PHASE2	UNKNOWN	Improvement of Peritoneal Catheter Placement in VPS With a Splitable Trocar
NCT00001327	Not specified	COMPLETED	Establishing the Physiology of Syringomyelia
NCT00280904	Not specified	COMPLETED	A Registry for Comparing Catheter-Related Infection Rates Among Various Shunt Systems in the Treatment of Hydrocephalus
NCT00651950	Not specified	WITHDRAWN	Bench Study of Transcutaneous Hydrocephalic Shunt Flow Sensor Alignment Accuracy and Repeatability
NCT00652197	Not specified	COMPLETED	Monitoring Patient Cerebro-Spinal Fluid Drainage With an Ultrasonic Flow Sensor
NCT00652249	Not specified	WITHDRAWN	Diagnosing Malfunctioning Hydrocephalic Shunt Valves With a Flow Sensor
NCT00692744	Not specified	COMPLETED	Quality of Life in Elderly After Aneurysmal Subarachnoid Hemorrhage (SAH)
NCT00743457	Not specified	COMPLETED	Study of Ultrasound of the Eye for Children With Suspected Shunt Failure
NCT00875758	Not specified	COMPLETED	Optimizing Treatment of Post-hemorrhagic Ventricular Dilation in Preterm Infants
NCT00886054	Not specified	UNKNOWN	The Prediction of Intracranial Pressure and Clinical Outcome by Transcranial Doppler in Neurocritical Patients
NCT00946127	Not specified	TERMINATED	ETV Versus Shunt Surgery in Normal Pressure Hydrocephalus
NCT01108965	Not specified	COMPLETED	Study of Shunt Flow Sensor Accuracy in Extra-ventricular Drains.
NCT01191307	Not specified	TERMINATED	Assess Specific Kinds of Children Challenges for Neurologic Devices Study
NCT01556178	Not specified	COMPLETED	Blood and Cerebrospinal Fluid for Pediatric Brain Tumor Research
NCT01797627	Not specified	COMPLETED	Ventricular Size Involvement in Neuropsychological Outcomes in Pediatric Hydrocephalus
NCT01799018	Not specified	COMPLETED	Role of Proteomics and Metallomics in Cerebral Vasospasm Following Subarachnoid Hemorrhage
NCT01811589	Not specified	COMPLETED	Guided Application of Ventricular Catheters
NCT01863329	Not specified	TERMINATED	Comparison of Optic Nerve Sheath Diameter on Retrobulbar Ultrasound Before and After Drainage of Cerebrospinal Fluid in Patient With Hydrocephalus
NCT01863381	Not specified	TERMINATED	Comparison of Continuous Non-Invasive and Invasive Intracranial Pressure Measurement
NCT01865149	Not specified	UNKNOWN	Comparison of Optic Nerve Sheath Diameter on Retrobulbar Ultrasonography Before and After Drainage of Cerebrospinal Fluid in Pediatric Patient With Hydrocephalus
NCT01973764	Not specified	TERMINATED	Intraventricular Drain Insertion: Comparison of Ultrasound-guided and Landmark-based Puncture of the Ventricular System
NCT01976559	Not specified	COMPLETED	Comparison of Continuous Noninvasive and Invasive Intracranial Pressure Measurement–Celda Infusion Subprotocol
NCT02067364	Not specified	UNKNOWN	CRT ShuntCheck Fit & Function Study
NCT02230124	Not specified	ACTIVE_NOT_RECRUITING	Magnetic Resonance Elastography in Hydrocephalus
NCT02381977	Not specified	COMPLETED	Prevalence of Acute Critical Neurological Disease in Children: a Global Epidemiological Assessment