PPFIBP1

Summary

PPFIBP1 (PPFIB scaffold protein 1, HGNC:9249) is a protein-coding gene on chromosome 12p11.23-p11.22, encoding Liprin-beta-1 (Q86W92). May regulate the disassembly of focal adhesions.

The protein encoded by this gene is a member of the LAR protein-tyrosine phosphatase-interacting protein (liprin) family. Liprins interact with members of LAR family of transmembrane protein tyrosine phosphatases, which are known to be important for axon guidance and mammary gland development. It has been proposed that liprins are multivalent proteins that form complex structures and act as scaffolds for the recruitment and anchoring of LAR family of tyrosine phosphatases. This protein was found to interact with S100A4, a calcium-binding protein related to tumor invasiveness and metastasis. In vitro experiment demonstrated that the interaction inhibited the phosphorylation of this protein by protein kinase C and protein kinase CK2. Alternatively spliced transcript variants encoding distinct isoforms have been reported.

Source: NCBI Gene 8496 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 204 total — 11 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 46
• MANE Select transcript: NM_003622

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9249
Approved symbol	PPFIBP1
Name	PPFIB scaffold protein 1
Location	12p11.23-p11.22
Locus type	gene with protein product
Status	Approved
Aliases	L2, hSGT2, hSgt2p, SGT2, liprin-beta1
Ensembl gene	ENSG00000110841
Ensembl biotype	protein_coding
OMIM	603141
Entrez	8496

Gene structure

Transcript identifiers

Ensembl transcripts: 61 — 56 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined, 1 non_stop_decay

ENST00000228425, ENST00000318304, ENST00000534917, ENST00000535047, ENST00000535575, ENST00000537261, ENST00000537927, ENST00000538433, ENST00000539326, ENST00000540114, ENST00000540256, ENST00000540503, ENST00000541633, ENST00000542187, ENST00000542629, ENST00000545334, ENST00000545381, ENST00000619325, ENST00000887718, ENST00000887719, ENST00000887720, ENST00000887721, ENST00000887722, ENST00000887723, ENST00000887724, ENST00000887725, ENST00000887726, ENST00000887727, ENST00000887728, ENST00000887729, ENST00000887730, ENST00000927416, ENST00000927417, ENST00000943182, ENST00000943183, ENST00000943184, ENST00000943185, ENST00000943186, ENST00000943187, ENST00000943188, ENST00000943189, ENST00000943190, ENST00000943191, ENST00000943192, ENST00000943193, ENST00000943194, ENST00000943195, ENST00000943196, ENST00000943197, ENST00000943198, ENST00000943199, ENST00000943200, ENST00000943201, ENST00000943202, ENST00000943203, ENST00000943204, ENST00000943205, ENST00000943206, ENST00000943207, ENST00000943208, ENST00000943209

RefSeq mRNA: 4 — MANE Select: NM_003622 NM_001198915, NM_001198916, NM_003622, NM_177444

CCDS: CCDS55812, CCDS55813, CCDS55814, CCDS8713

Canonical transcript exons

ENST00000228425 — 30 exons

Exon	Start	End
ENSE00000733644	27654722	27654814
ENSE00000733645	27656616	27656730
ENSE00000733649	27667166	27667320
ENSE00000733651	27671431	27671546
ENSE00000733652	27672427	27672483
ENSE00000733660	27682615	27682703
ENSE00000733661	27687385	27687507
ENSE00000835940	27660884	27660945
ENSE00000835948	27676428	27676599
ENSE00000835950	27679933	27680061
ENSE00000835955	27688298	27688423
ENSE00000835957	27691749	27691928
ENSE00000835958	27692591	27692656
ENSE00001008006	27674192	27674221
ENSE00001188879	27578152	27578239
ENSE00001238451	27677064	27677096
ENSE00001238517	27664362	27664446
ENSE00001238579	27634910	27635115
ENSE00001388186	27679489	27679639
ENSE00001388532	27673767	27673827
ENSE00002249125	27524206	27524365
ENSE00002269114	27692796	27695564
ENSE00003497357	27650010	27650141
ENSE00003503848	27681546	27681696
ENSE00003537805	27689015	27689203
ENSE00003554147	27633362	27633460
ENSE00003614020	27646062	27646148
ENSE00003627989	27682387	27682498
ENSE00003690120	27647729	27647842
ENSE00003789097	27658816	27658848

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 98.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.6659 / max 879.6430, expressed in 1715 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
124840	34.6659	1715

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	98.81	gold quality
sural nerve	UBERON:0015488	97.28	gold quality
tendon	UBERON:0000043	97.16	gold quality
buccal mucosa cell	CL:0002336	97.09	gold quality
colonic epithelium	UBERON:0000397	96.77	gold quality
left ovary	UBERON:0002119	96.59	gold quality
calcaneal tendon	UBERON:0003701	96.50	gold quality
trigeminal ganglion	UBERON:0001675	95.77	gold quality
ovary	UBERON:0000992	95.58	gold quality
cardiac ventricle	UBERON:0002082	95.50	gold quality
heart left ventricle	UBERON:0002084	95.49	gold quality
heart right ventricle	UBERON:0002080	95.40	gold quality
nipple	UBERON:0002030	95.26	gold quality
descending thoracic aorta	UBERON:0002345	95.17	gold quality
cervix squamous epithelium	UBERON:0006922	94.97	gold quality
dorsal root ganglion	UBERON:0000044	94.90	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.68	gold quality
right ovary	UBERON:0002118	94.63	gold quality
pericardium	UBERON:0002407	94.55	gold quality
thoracic aorta	UBERON:0001515	94.32	gold quality
metanephros cortex	UBERON:0010533	94.29	gold quality
adrenal tissue	UBERON:0018303	94.28	gold quality
ascending aorta	UBERON:0001496	94.24	gold quality
apex of heart	UBERON:0002098	94.04	gold quality
heart	UBERON:0000948	93.93	gold quality
renal medulla	UBERON:0000362	93.90	gold quality
thyroid gland	UBERON:0002046	93.50	gold quality
left lobe of thyroid gland	UBERON:0001120	93.44	gold quality
vena cava	UBERON:0004087	93.38	gold quality
right lung	UBERON:0002167	93.37	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	3019.90
E-MTAB-10137	yes	1566.78
E-MTAB-8142	yes	592.75
E-HCAD-1	yes	445.07
E-MTAB-10553	yes	44.44
E-GEOD-135922	yes	25.84
E-CURD-119	yes	24.30
E-HCAD-35	yes	20.46
E-MTAB-6701	yes	17.90
E-CURD-46	yes	14.71
E-MTAB-8410	yes	13.39
E-GEOD-130148	yes	9.01
E-GEOD-83139	yes	6.92
E-CURD-112	no	2.86
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

137 targeting PPFIBP1, 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-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-9718	99.94	68.91	918

Literature-anchored findings (GeneRIF, showing 8)

• new molecular target of the S100A4 protein, liprin beta1 (PMID:11836260)
• liprin beta1, a member of the family of LAR transmembrane tyrosine phosphatase-interacting proteins, as highly expressed in intestinal lymphatic endothelial cells in vitro and lymphatic vasculature in vivo (PMID:19965622)
• Novel ALK fusions are being identified in various tumors in addition to inflammatory myofibroblastic tumor. (PMID:21430068)
• Liprins can mediate assembly of target proteins into large protein complexes capable of regulating numerous cellular activities. (PMID:21855798)
• Analysis of the role of liprin-beta1 and liprin-beta2 has shown that while liprin-beta1 contributes positively to tumour cell motility in vitro; liprin-beta2 has a negative effect on both cell motility and invasion. (PMID:26663347)
• liprin beta-1 is associated with expression of kank 1 and 2 proteins in melanoma (PMID:26739330)
• PPFIBP1 induces glioma cell migration and invasion through FAK/Src/JNK signaling pathway. (PMID:34480020)
• A novel homozygous truncating variant in PPFIBP1 further delineates PPFIBP1-associated neurodevelopmental disorder. (PMID:36527195)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppfibp1a	ENSDARG00000045749
danio_rerio	ppfibp1b	ENSDARG00000100057
mus_musculus	Ppfibp1	ENSMUSG00000016487
rattus_norvegicus	Ppfibp1	ENSRNOG00000031709
drosophila_melanogaster	Liprin-beta	FBGN0036376
caenorhabditis_elegans		WBGENE00011904

Paralogs (5): PPFIA1 (ENSG00000131626), PPFIA2 (ENSG00000139220), PPFIA4 (ENSG00000143847), PPFIBP2 (ENSG00000166387), PPFIA3 (ENSG00000177380)

Protein

Protein identifiers

Liprin-beta-1 — Q86W92 (reviewed: Q86W92)

Alternative names: Protein tyrosine phosphatase receptor type f polypeptide-interacting protein-binding protein 1, hSGT2

All UniProt accessions (10): Q86W92, A0A087WVX8, A0A0A0MTP2, F5GZP6, F5H0E0, F5H495, F5H6Q7, F5H7K5, H0YFE4, H0YGH8

UniProt curated annotations — full annotation on UniProt →

Function. May regulate the disassembly of focal adhesions. Did not bind receptor-like tyrosine phosphatases type 2A.

Subunit / interactions. Forms homodimers and heterodimers. Interacts with S100A4 in a Ca(2+)-dependent mode. Part of a cortical microtubule stabilization complex (CMSC) composed of KANK1, PPFIA1, PPFIBP1, ERC1/ELKS, PHLDB2/LL5beta, CLASPs, KIF21A and possibly additional interactors; within CMSCs KANK1 and PHLDB2/LL5beta seem to be the core components for recruiting microtubule-binding proteins KIF21A and CLASPs, whereas PPFIA1, PPFIBP1 and ERC1/ELKS serve as scaffolds for protein clustering. Interacts with KANK1 (via CC1 domain, residues 244-339).

Subcellular location. Cytoplasm. Cell cortex.

Tissue specificity. Widely expressed. Absent in liver.

Disease relevance. Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities (NEDSMBA) [MIM:620024] An autosomal recessive disorder characterized by global developmental delay, severe to profound intellectual disability, progressive microcephaly, refractory early-onset epilepsy, white matter abnormalities, and periventricular calcifications. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The N-terminal coiled coil regions mediate homodimerization preferentially and heterodimerization type beta/beta. The C-terminal, non-coiled coil regions mediate heterodimerization type beta/alpha and interaction with S100A4.

Miscellaneous. Due to intron retention.

Similarity. Belongs to the liprin family. Liprin-beta subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
Q86W92-1	1	yes
Q86W92-2	2
Q86W92-3	3
Q86W92-4	4
Q86W92-5	5, L2

RefSeq proteins (4): NP_001185844, NP_001185845, NP_003613, NP_803193 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001660	SAM	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR029515	Liprin	Family
IPR037617	LIPB1/2_SAM_1	Domain
IPR037618	LIPB1/2_SAM_2nd	Domain
IPR037619	LIPB1/2_SAM_3rd	Domain
IPR058914	LIPB1/2_CC	Domain

Pfam: PF00536, PF07647, PF26022

UniProt features (44 total): modified residue 16, splice variant 7, sequence variant 7, domain 3, sequence conflict 3, compositionally biased region 3, region of interest 2, chain 1, cross-link 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86W92-F1	67.83	0.26

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 (17): 37, 39, 40, 322, 434, 466, 540, 579, 601, 636, 794, 999, 1001, 1003, 1005, 471, 523

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-388844	Receptor-type tyrosine-protein phosphatases
R-HSA-9725370	Signaling by ALK fusions and activated point mutants
R-HSA-112316	Neuronal System
R-HSA-1643685	Disease
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-6794362	Protein-protein interactions at synapses
R-HSA-9700206	Signaling by ALK in cancer

MSigDB gene sets: 328 (showing top): GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, GOBP_CYTOPLASMIC_MICROTUBULE_ORGANIZATION, NKX25_02, JOHANSSON_GLIOMAGENESIS_BY_PDGFB_UP, HNF1_Q6, GRAHAM_CML_QUIESCENT_VS_NORMAL_QUIESCENT_DN, chr12p11, GOBP_CELL_JUNCTION_ORGANIZATION, VERNELL_RETINOBLASTOMA_PATHWAY_DN, CADWELL_ATG16L1_TARGETS_DN, FOSTER_TOLERANT_MACROPHAGE_UP, TGACATY_UNKNOWN, ATF3_Q6, SENESE_HDAC1_TARGETS_UP

GO Biological Process (3): cell adhesion (GO:0007155), neuromuscular junction development (GO:0007528), cortical microtubule organization (GO:0043622)

GO Molecular Function (2): cadherin binding (GO:0045296), protein binding (GO:0005515)

GO Cellular Component (6): cytosol (GO:0005829), plasma membrane (GO:0005886), focal adhesion (GO:0005925), cell cortex (GO:0005938), presynaptic active zone (GO:0048786), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Protein-protein interactions at synapses	1
Signaling by ALK in cancer	1
Disease	1
Neuronal System	1
Diseases of signal transduction by growth factor receptors and second messengers	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	2
cell periphery	2
cellular process	1
synapse organization	1
cortical cytoskeleton organization	1
cytoplasmic microtubule organization	1
cell adhesion molecule binding	1
binding	1
membrane	1
cell-substrate junction	1
presynapse	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

936 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPFIBP1	PTPRF	P10586	917
PPFIBP1	PTPRS	Q13332	737
PPFIBP1	PPFIA1	Q13136	716
PPFIBP1	SMCO2	A6NFE2	692
PPFIBP1	ERC1	Q8IUD2	691
PPFIBP1	KANK1	Q14678	679
PPFIBP1	PTPRD	P23468	662
PPFIBP1	KANK2	Q63ZY3	653
PPFIBP1	GRIP1	Q9Y3R0	543
PPFIBP1	PWWP2A	Q96N64	522
PPFIBP1	PPFIA3	O75145	478
PPFIBP1	S100A4	P26447	478
PPFIBP1	SEC31A	O94979	476
PPFIBP1	GRIA1	P42261	476
PPFIBP1	PPFIA2	O75334	469

IntAct

142 interactions, top by confidence:

A	B	Type	Score
YWHAG	PPFIBP1	psi-mi:“MI:0915”(physical association)	0.870
YWHAQ	WDR62	psi-mi:“MI:0914”(association)	0.830
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
PPFIBP1	YWHAH	psi-mi:“MI:0914”(association)	0.740
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
PRKAB2	GYS1	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PPFIBP1	YWHAZ	psi-mi:“MI:0915”(physical association)	0.690
rep	PPFIBP1	psi-mi:“MI:0915”(physical association)	0.670
PPFIBP1	YWHAE	psi-mi:“MI:0915”(physical association)	0.650
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
DYNLL2	BLTP3B	psi-mi:“MI:0914”(association)	0.640
SFN	PPFIBP1	psi-mi:“MI:0915”(physical association)	0.630
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAB	BLTP3B	psi-mi:“MI:0914”(association)	0.610
ADRA1D	LIN7A	psi-mi:“MI:0914”(association)	0.590
YWHAE	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAZ	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
PBX2	PPFIBP1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (248): PPFIBP1 (Affinity Capture-RNA), PPFIBP1 (Affinity Capture-RNA), PPFIBP1 (Affinity Capture-RNA), PPFIBP1 (Affinity Capture-MS), PPFIBP1 (Affinity Capture-MS), PPFIBP1 (Two-hybrid), PPFIBP1 (Two-hybrid), PPFIBP1 (Two-hybrid), PPFIBP1 (Proximity Label-MS), PPFIBP1 (Affinity Capture-MS), PPFIBP1 (Affinity Capture-MS), PPFIBP1 (Affinity Capture-MS), PPFIBP1 (Affinity Capture-MS), PPFIBP1 (Affinity Capture-MS), PPFIBP1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8GUX5, A0A1L8GXY6, A0A1W2P884, A2CE83, B8A5S6, E7F5E1, F7DP49, H2MTR9, O08970, O35711, O60296, P27628, P53564, P60853, Q0VF96, Q28GJ0, Q2KJD6, Q3UIJ9, Q4V7D3, Q5BIX7, Q5R923, Q5SXA9, Q5SZL2, Q5U2Y9, Q5U4W1, Q5ZLT3, Q6AW69, Q6DIS8, Q6DJR2, Q6NRW2, Q6NXJ0, Q6P402, Q6PCQ0, Q6PD31, Q7TQE6, Q80ST9, Q86W92, Q8BMK0, Q8C8U0, Q8CFC9

Diamond homologs: A9C3W3, O35711, O75145, O75334, O75335, P60469, Q13136, Q21049, Q5FWS6, Q674X7, Q69ZS8, Q86W92, Q8BSS9, Q8C8U0, Q8ND30, Q91Z79, Q91Z80, Q94071

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 140 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	57.3×	3e-09
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	50.6×	5e-09
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	50.6×	5e-09
Activation of BH3-only proteins	7	37.4×	4e-08
Intrinsic Pathway for Apoptosis	8	25.2×	6e-08
RHO GTPases activate PKNs	7	23.9×	8e-07
RAF activation	6	21.7×	1e-05
Translocation of SLC2A4 (GLUT4) to the plasma membrane	11	18.2×	3e-09

GO biological processes:

GO term	Partners	Fold	FDR
visual learning	6	14.6×	3e-03
protein targeting	5	14.5×	7e-03
substantia nigra development	5	14.5×	7e-03
intracellular protein localization	8	6.7×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	1
Uncertain significance	140
Likely benign	19
Benign	1

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
1679175	NM_003622.4(PPFIBP1):c.1146+1G>A	Pathogenic
1679176	NM_003622.4(PPFIBP1):c.2654del (p.Tyr885fs)	Pathogenic
1679177	NM_003622.4(PPFIBP1):c.1368_1369del (p.Glu456fs)	Pathogenic
1679178	NM_003622.4(PPFIBP1):c.2413C>T (p.Arg805Ter)	Pathogenic
1679179	NM_003622.4(PPFIBP1):c.1468C>T (p.Gln490Ter)	Pathogenic
1679180	NM_003622.4(PPFIBP1):c.403C>T (p.Arg135Ter)	Pathogenic
1679181	NM_003622.4(PPFIBP1):c.1417_1427del (p.Ala473fs)	Pathogenic
1679182	NM_003622.4(PPFIBP1):c.1300C>T (p.Gln434Ter)	Pathogenic
1679183	NM_003622.4(PPFIBP1):c.2629C>T (p.Arg877Ter)	Pathogenic
1691862	NM_003622.4(PPFIBP1):c.2158+2T>C	Pathogenic
3254872	NM_003622.4(PPFIBP1):c.170del (p.Gly57fs)	Pathogenic
3063807	NM_003622.4(PPFIBP1):c.358-2_358-1delinsCC	Likely pathogenic

SpliceAI

5308 predictions. Top by Δscore:

Variant	Effect	Δscore
12:27524363:CAGGT:C	donor_loss	1.0000
12:27524364:AGGT:A	donor_loss	1.0000
12:27524366:G:GG	donor_gain	1.0000
12:27524366:GT:G	donor_loss	1.0000
12:27578148:TCAG:T	acceptor_loss	1.0000
12:27578149:CAG:C	acceptor_loss	1.0000
12:27578150:A:AG	acceptor_gain	1.0000
12:27578150:AGTA:A	acceptor_loss	1.0000
12:27578151:G:A	acceptor_loss	1.0000
12:27578151:G:GC	acceptor_gain	1.0000
12:27578151:GT:G	acceptor_gain	1.0000
12:27578151:GTA:G	acceptor_gain	1.0000
12:27578151:GTAT:G	acceptor_gain	1.0000
12:27578151:GTATA:G	acceptor_gain	1.0000
12:27578235:AAAAT:A	donor_gain	1.0000
12:27578236:AAAT:A	donor_gain	1.0000
12:27578236:AAATG:A	donor_loss	1.0000
12:27578237:AAT:A	donor_gain	1.0000
12:27578237:AATGT:A	donor_loss	1.0000
12:27578238:AT:A	donor_gain	1.0000
12:27578238:ATGTA:A	donor_loss	1.0000
12:27578239:TGT:T	donor_loss	1.0000
12:27578240:G:GA	donor_loss	1.0000
12:27578240:G:GG	donor_gain	1.0000
12:27578241:TAAG:T	donor_loss	1.0000
12:27621720:T:G	donor_gain	1.0000
12:27646060:A:AG	acceptor_gain	1.0000
12:27646061:G:GG	acceptor_gain	1.0000
12:27646061:GAC:G	acceptor_gain	1.0000
12:27646061:GACAA:G	acceptor_gain	1.0000

AlphaMissense

6654 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:27681656:G:A	G675D	1.000
12:27682617:T:A	W727R	1.000
12:27682617:T:C	W727R	1.000
12:27682621:T:C	L728S	1.000
12:27682632:G:C	G732R	1.000
12:27682636:T:C	L733P	1.000
12:27687430:A:C	S771R	1.000
12:27687432:T:A	S771R	1.000
12:27687432:T:G	S771R	1.000
12:27687455:T:C	L779P	1.000
12:27688328:T:A	W807R	1.000
12:27688328:T:C	W807R	1.000
12:27688352:T:A	W815R	1.000
12:27688352:T:C	W815R	1.000
12:27688356:T:C	L816P	1.000
12:27688392:T:C	L828P	1.000
12:27688404:G:A	G832D	1.000
12:27688407:T:A	V833D	1.000
12:27688412:G:C	G835R	1.000
12:27688413:G:A	G835D	1.000
12:27688419:T:C	L837P	1.000
12:27689031:T:C	F844S	1.000
12:27692622:T:A	I972K	1.000
12:27692652:T:A	L982Q	1.000
12:27692652:T:C	L982P	1.000
12:27692803:T:C	L986S	1.000
12:27681563:T:C	F644S	0.999
12:27681571:T:A	W647R	0.999
12:27681571:T:C	W647R	0.999
12:27681595:T:A	W655R	0.999

dbSNP variants (sampled 300 via entrez): RS1000024008 (12:27531804 T>C), RS1000072787 (12:27585564 G>A,C), RS1000085404 (12:27575782 G>A), RS1000087249 (12:27655800 A>C), RS1000091028 (12:27532504 C>T), RS1000105650 (12:27615193 A>C), RS1000112287 (12:27525354 C>A), RS1000114333 (12:27614356 C>A), RS1000116080 (12:27592569 A>C,G,T), RS1000118508 (12:27656114 G>A), RS1000131999 (12:27530977 G>A), RS1000132636 (12:27524713 A>C), RS1000183046 (12:27526981 G>A,C), RS1000185315 (12:27524461 C>T), RS1000226974 (12:27543582 C>T)

Disease associations

OMIM: gene MIM:603141 | disease phenotypes: MIM:620024

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities	Strong	Autosomal recessive
neurodevelopmental disorder	Strong	Autosomal recessive

Mondo (3): microcephaly (MONDO:0001149), neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities (MONDO:0859283), neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

46 total (30 of 46 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000122	Unilateral renal agenesis
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000639	Nystagmus
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001276	Hypertonia
HP:0001302	Pachygyria
HP:0001320	Cerebellar vermis hypoplasia
HP:0001332	Dystonia
HP:0001344	Absent speech
HP:0001508	Failure to thrive
HP:0001518	Small for gestational age
HP:0001629	Ventricular septal defect
HP:0001631	Atrial septal defect
HP:0001643	Patent ductus arteriosus
HP:0002079	Hypoplasia of the corpus callosum
HP:0002119	Ventriculomegaly
HP:0002120	Cerebral cortical atrophy
HP:0002197	Generalized-onset seizure
HP:0002282	Gray matter heterotopia
HP:0002352	Leukoencephalopathy
HP:0002384	Focal impaired awareness seizure
HP:0002510	Spastic tetraplegia
HP:0002514	Cerebral calcification
HP:0002521	Hypsarrhythmia

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004138_3	Early-onset Parkinson’s disease	1.000000e-33
GCST006223_5	Cerebral cortical growth	9.000000e-06
GCST010002_212	Refractive error	2.000000e-13
GCST012490_341	Femur bone mineral density x serum urate levels interaction	3.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement

MeSH disease descriptors (2)

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
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	3
Valproic Acid	affects expression, decreases expression, increases expression	3
bisphenol A	affects cotreatment, decreases expression, decreases methylation	2
Caffeine	decreases phosphorylation, increases expression	2
Cisplatin	increases expression	2
Dexamethasone	decreases expression, affects cotreatment	2
Nickel	decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Cyclosporine	decreases expression, increases expression	2
Aflatoxin B1	increases expression, increases methylation	2
Cadmium Chloride	decreases expression, increases expression	2
FR900359	affects phosphorylation	1
chloroacetaldehyde	decreases expression	1
methylmercuric chloride	decreases expression, increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, decreases expression	1
cinnamaldehyde	increases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
coumarin	affects phosphorylation	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
avobenzone	increases expression	1
cylindrospermopsin	increases expression	1
CGP 52608	increases reaction, affects binding	1
monomethylarsonous acid	increases expression	1
torcetrapib	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice