NFASC

Summary

NFASC (neurofascin, HGNC:29866) is a protein-coding gene on chromosome 1q32.1, encoding Neurofascin (O94856). Cell adhesion, ankyrin-binding protein which may be involved in neurite extension, axonal guidance, synaptogenesis, myelination and neuron-glial cell interactions.

This gene encodes an L1 family immunoglobulin cell adhesion molecule with multiple IGcam and fibronectin domains. The protein functions in neurite outgrowth, neurite fasciculation, and organization of the axon initial segment (AIS) and nodes of Ranvier on axons during early development. Both the AIS and nodes of Ranvier contain high densities of voltage-gated Na+ (Nav) channels which are clustered by interactions with cytoskeletal and scaffolding proteins including this protein, gliomedin, ankyrin 3 (ankyrin-G), and betaIV spectrin. This protein links the AIS extracellular matrix to the intracellular cytoskeleton. This gene undergoes extensive alternative splicing, and the full-length nature of some variants has not been determined.

Source: NCBI Gene 23114 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with central and peripheral motor dysfunction (Strong, GenCC)
• GWAS associations: 14
• Clinical variants (ClinVar): 348 total — 9 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 37
• MANE Select transcript: NM_001005388

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29866
Approved symbol	NFASC
Name	neurofascin
Location	1q32.1
Locus type	gene with protein product
Status	Approved
Aliases	NRCAML, KIAA0756, FLJ46866, NF
Ensembl gene	ENSG00000163531
Ensembl biotype	protein_coding
OMIM	609145
Entrez	23114

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 18 protein_coding, 7 protein_coding_CDS_not_defined, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000339876, ENST00000367173, ENST00000401399, ENST00000403080, ENST00000404076, ENST00000404977, ENST00000413225, ENST00000425360, ENST00000430393, ENST00000447819, ENST00000468328, ENST00000471392, ENST00000492085, ENST00000493914, ENST00000495396, ENST00000503221, ENST00000504149, ENST00000504476, ENST00000505079, ENST00000512826, ENST00000513543, ENST00000514644, ENST00000539706, ENST00000680427, ENST00000903183, ENST00000903184, ENST00000903185, ENST00000927203, ENST00000944486

RefSeq mRNA: 10 — MANE Select: NM_001005388 NM_001005388, NM_001005389, NM_001160331, NM_001160332, NM_001160333, NM_001365986, NM_001378329, NM_001378330, NM_001378331, NM_015090

CCDS: CCDS30982, CCDS53460, CCDS53461, CCDS53462, CCDS91149, CCDS91150

Canonical transcript exons

ENST00000339876 — 30 exons

Exon	Start	End
ENSE00001381834	205001170	205001286
ENSE00001387032	204997170	204997406
ENSE00002247220	204920632	204920740
ENSE00002369906	204950557	204950574
ENSE00003478550	205012797	205012866
ENSE00003519684	204974179	204974290
ENSE00003530582	204973276	204973419
ENSE00003531161	204979362	204979559
ENSE00003557412	204987418	204987540
ENSE00003569578	204968798	204968982
ENSE00003573258	204952011	204952116
ENSE00003575698	204975271	204975418
ENSE00003579245	204976671	204976795
ENSE00003582314	204954188	204954384
ENSE00003586096	205009557	205009688
ENSE00003588436	204980370	204980440
ENSE00003592309	204977681	204977725
ENSE00003593299	205016308	205022822
ENSE00003597057	204968249	204968360
ENSE00003609304	204957656	204957826
ENSE00003619544	204944226	204944406
ENSE00003632817	204981798	204982020
ENSE00003643528	204970616	204970747
ENSE00003647562	204978968	204979069
ENSE00003655261	204988633	204988806
ENSE00003660211	204974657	204974823
ENSE00003672454	205002596	205002748
ENSE00003678392	204991292	204991306
ENSE00003684060	204954829	204954951
ENSE00003915106	204828652	204828782

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 97.78.

FANTOM5 (CAGE): breadth broad, TPM avg 14.5600 / max 450.8731, expressed in 907 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
7990	13.0211	906
7996	0.8898	87
7994	0.4430	85
7993	0.0888	34
7997	0.0732	45
7995	0.0441	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
inferior olivary complex	UBERON:0002127	97.78	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.60	gold quality
lateral globus pallidus	UBERON:0002476	97.44	gold quality
corpus callosum	UBERON:0002336	97.25	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	96.67	gold quality
inferior vagus X ganglion	UBERON:0005363	96.43	gold quality
renal glomerulus	UBERON:0000074	96.41	gold quality
metanephric glomerulus	UBERON:0004736	96.27	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.24	gold quality
substantia nigra pars compacta	UBERON:0001965	96.17	gold quality
medulla oblongata	UBERON:0001896	95.81	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.74	gold quality
middle frontal gyrus	UBERON:0002702	95.71	gold quality
subthalamic nucleus	UBERON:0001906	95.70	gold quality
dorsal plus ventral thalamus	UBERON:0001897	95.68	gold quality
globus pallidus	UBERON:0001875	95.57	gold quality
postcentral gyrus	UBERON:0002581	95.42	gold quality
primary visual cortex	UBERON:0002436	95.33	gold quality
CA1 field of hippocampus	UBERON:0003881	95.27	gold quality
sural nerve	UBERON:0015488	95.23	gold quality
parietal lobe	UBERON:0001872	95.20	gold quality
medial globus pallidus	UBERON:0002477	95.18	gold quality
occipital lobe	UBERON:0002021	94.98	gold quality
superior vestibular nucleus	UBERON:0007227	94.96	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.64	gold quality
Ammon’s horn	UBERON:0001954	94.62	gold quality
entorhinal cortex	UBERON:0002728	94.54	gold quality
ventral tegmental area	UBERON:0002691	94.48	gold quality
orbitofrontal cortex	UBERON:0004167	94.37	gold quality
superior frontal gyrus	UBERON:0002661	94.08	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	32.65
E-ANND-3	yes	7.73

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

397 targeting NFASC, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4745-5P	99.98	65.95	1028

Literature-anchored findings (GeneRIF, showing 22)

• different splicing variants of NF expressed on neurons and glia play distinct roles during neural development (PMID:16061393)
• raft-association of NF155 is essential for the assembly of the paranodal junction and reduced association to lipid rafts is accompanied by the disassembly of the paranodal junction and contributes to the demyelination process in multiple sclerosis (PMID:17405145)
• antibodies to neurofascin selectively targeted nodes of Ranvier, resulting in deposition of complement, axonal injury, and disease exacerbation (PMID:17846150)
• a neurofascin intracellular domain activates FGFR1 for neurite outgrowth, whereas the extracellular domain functions as an additional, regulatory FGFR1 interaction domain in the course of development (PMID:19666467)
• in both mouse and human samples, the expression pattern of neurofascin 155(high) and neurofascin 155(low) is altered coincident with paranodal decay. (PMID:20129933)
• Nfasc isoforms use distinct protein-protein interaction modules to organize and stabilize specific axonal domains in myelinated axons. Loss of Nfasc immunoglobulin domains 5 and 6 in transgenic mice mimics complete ablation of Nfasc. (PMID:20371806)
• two crystal structures of a dimeric form of the headpiece of neurofascin (PMID:21047790)
• Fibronectin type III-like domains of neurofascin-186 protein mediate gliomedin binding and its clustering at the developing nodes of Ranvier (PMID:22009740)
• Neurofascin isoforms of 186, 180, 166 and 155 kDa are generated by alternative splicing and provide a switch between neuronal plasticity and stability. (Review) (PMID:22306302)
• gliomedin, NF186, and contactin are novel target antigens in Guillain-Barre syndrome (PMID:22462667)
• Cerebellar pinceau organization requires coordinated mechanisms involving specific neurofascin functions in both Purkinje and basket neurons. (PMID:22492029)
• Three neuronal proteins (Huntingtin interacting protein 1, neurofascin, and olfactomedin-like 2a) are novel components of podocyte major processes and their expression in glomerular crescents supports their role in crescent formation. (PMID:22913984)
• Anti-neurofascin antibody is frequently present in patients with CCPD. (PMID:23884033)
• Autoantibodies to NF155 identify a inflammatory demyelinating polyradiculoneuropathy subtype characterized by severe neuropathy, poor response to intravenous immunoglobulin, and disabling tremor. (PMID:24523485)
• It is a common protein to the central and peripheral nervous system may play a pivotal role in combined demyelination in Combined central and peripheral demyelination. (PMID:25672685)
• -NF155 IgG4 antibodies were associated with a subgroup of patients with CIDP showing a younger age at onset, ataxia, tremor, CNS demyelination, and a poor response to IV immunoglobulin. (PMID:26843559)
• data suggest that NFASC is a novel regulator of non-small cell lung cancer cell motility and support a role of NFASC in the regulation of non-small cell lung cancer progression (PMID:28418179)
• identified neurofascin as the target of the autoantibodies in Chronic inflammatory demyelination polyneuropathy patients. (PMID:28575198)
• A novel homozygous NFASC mutation chr1:204953187-C>T (rs755160624) is described. The variant creates a premature stop codon in 3 out of four NFASC human transcripts and is predicted to specifically eliminate Nfasc155 leaving neuronal Neurofascin intact. The selective absence of Nfasc155 and disruption of the paranodal junction was confirmed in patient. (PMID:30124836)
• we describe two affected siblings from a consanguineous Italian family presenting with infantile-onset ataxia and mild demyelinating polyneuropathy who carry a homozygous NFASC missense mutation. (PMID:30850329)
• The results link biallelic variants in NFASC isoforms at glial cells to defects in the paranodal axoglial junctions and phenotypes that range from variable neurodevelopmental impairment to weakness, central hypomyelination, and peripheral chronic demyelinating neuropathy. (PMID:31501903)
• Case report of two children with auditory neuropathy spectrum disorder related to a neurofascin (NFASC) gene variant. (PMID:31945734)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000056910
danio_rerio	nfasca	ENSDARG00000061099
mus_musculus	Nfasc	ENSMUSG00000026442
rattus_norvegicus	Nfasc	ENSRNOG00000030515

Paralogs (36): CNTN1 (ENSG00000018236), CDON (ENSG00000064309), NEO1 (ENSG00000067141), SDK2 (ENSG00000069188), IGSF9B (ENSG00000080854), IGSF9 (ENSG00000085552), NRCAM (ENSG00000091129), MXRA5 (ENSG00000101825), IGDCC4 (ENSG00000103742), CNTN3 (ENSG00000113805), IGSF21 (ENSG00000117154), CNTN6 (ENSG00000134115), CHL1 (ENSG00000134121), PTPRQ (ENSG00000139304), CNTN4 (ENSG00000144619), BOC (ENSG00000144857), SDK1 (ENSG00000146555), HMCN2 (ENSG00000148357), NCAM1 (ENSG00000149294), CNTN5 (ENSG00000149972), IGSF10 (ENSG00000152580), ROBO4 (ENSG00000154133), ROBO3 (ENSG00000154134), NCAM2 (ENSG00000154654), VCAM1 (ENSG00000162692), PRTG (ENSG00000166450), ROBO1 (ENSG00000169855), DSCAM (ENSG00000171587), IGDCC3 (ENSG00000174498), VSIG10 (ENSG00000176834), DSCAML1 (ENSG00000177103), CNTN2 (ENSG00000184144), ROBO2 (ENSG00000185008), VSIG10L (ENSG00000186806), DCC (ENSG00000187323), L1CAM (ENSG00000198910)

Protein

Protein identifiers

Neurofascin — O94856 (reviewed: O94856)

All UniProt accessions (9): A0A0C4DG92, A0A7P0Z4R6, O94856, D6RBU5, D6RHX4, H7BY57, H7C073, H7C0L6, X6RKN2

UniProt curated annotations — full annotation on UniProt →

Function. Cell adhesion, ankyrin-binding protein which may be involved in neurite extension, axonal guidance, synaptogenesis, myelination and neuron-glial cell interactions.

Subunit / interactions. Horseshoe-shaped homodimer. Probable constituent of a NFASC/NRCAM/ankyrin-G complex. Associates with the sodium channel beta-1 (SCN1B) and beta-3 (SCN3B) subunits. Interacts with GLDN/gliomedin. Interacts with MYOC.

Subcellular location. Cell membrane Cell junction. Paranodal septate junction.

Disease relevance. Neurodevelopmental disorder with central and peripheral motor dysfunction (NEDCPMD) [MIM:618356] An autosomal recessive neurodevelopmental disorder with early onset and a highly variable phenotype. Disease features include hypotonia apparent from birth, poor feeding, global developmental delay with absence of reaction to touch and no eye contact, infantile-onset progressive ataxia and demyelinating peripheral neuropathy. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Homophilic adhesion is primarily mediated by the interaction of the second Ig-like domains.

Miscellaneous. May be due to intron retention. May be due to intron retention.

Similarity. Belongs to the immunoglobulin superfamily. L1/neurofascin/NgCAM family.

Isoforms (13)

UniProt ID	Names	Canonical?
O94856-1	1	yes
O94856-2	2
O94856-3	3
O94856-4	4
O94856-5	5
O94856-6	6
O94856-7	7
O94856-8	8, Nfasc155
O94856-9	9
O94856-10	10
O94856-11	11
O94856-12	12
O94856-13	13

RefSeq proteins (10): NP_001005388, NP_001005389, NP_001153803, NP_001153804, NP_001153805, NP_001352915, NP_001365258, NP_001365259, NP_001365260, NP_055905 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR003961	FN3_dom	Domain
IPR007110	Ig-like_dom	Domain
IPR013098	Ig_I-set	Domain
IPR013151	Immunoglobulin_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR026965	NFASC_Ig-like	Domain
IPR026966	Neurofascin/L1/NrCAM_C	Domain
IPR036116	FN3_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily

Pfam: PF00041, PF00047, PF07679, PF13882, PF13927

UniProt features (111 total): strand 33, splice variant 14, domain 11, modified residue 9, glycosylation site 8, helix 6, disulfide bond 6, region of interest 5, compositionally biased region 5, sequence variant 4, turn 3, topological domain 2, sequence conflict 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3P3Y	X-RAY DIFFRACTION	2.6
3P40	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94856-F1	77.23	0.41

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 (9): 481, 485, 1267, 1281, 1294, 1297, 1333, 1334, 1338

Disulfide bonds (6): 63–118, 162–213, 268–316, 358–408, 452–501, 543–592

Glycosylation sites (8): 305, 409, 446, 483, 752, 778, 973, 988

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-445095	Interaction between L1 and Ankyrins
R-HSA-447043	Neurofascin interactions
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 332 (showing top): GGGACCA_MIR133A_MIR133B, TGGTGCT_MIR29A_MIR29B_MIR29C, AAGCAAT_MIR137, WALLACE_PROSTATE_CANCER_RACE_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GGTGTGT_MIR329, GOCC_SECRETORY_GRANULE, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GOBP_NEUROGENESIS, GOBP_CELL_CELL_ADHESION, BROWNE_HCMV_INFECTION_48HR_DN, CAGCAGG_MIR370, CHEOK_RESPONSE_TO_MERCAPTOPURINE_DN, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_ENSHEATHMENT_OF_NEURONS

GO Biological Process (6): axon guidance (GO:0007411), brain development (GO:0007420), peripheral nervous system development (GO:0007422), myelination (GO:0042552), cell-cell adhesion (GO:0098609), cell adhesion (GO:0007155)

GO Molecular Function (2): cell-cell adhesion mediator activity (GO:0098632), protein binding (GO:0005515)

GO Cellular Component (10): plasma membrane (GO:0005886), focal adhesion (GO:0005925), axon (GO:0030424), paranodal junction (GO:0033010), node of Ranvier (GO:0033268), axon initial segment (GO:0043194), ficolin-1-rich granule membrane (GO:0101003), membrane (GO:0016020), anchoring junction (GO:0070161), cell periphery (GO:0071944)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
L1CAM interactions	2
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
main axon	2
axonogenesis	1
neuron projection guidance	1
central nervous system development	1
animal organ development	1
head development	1
nervous system development	1
system development	1
axon ensheathment	1
cell adhesion	1
cellular process	1
cell-cell adhesion	1
cell adhesion mediator activity	1
binding	1
membrane	1
cell periphery	1
cell-substrate junction	1
neuron projection	1
cell-cell junction	1
secretory granule membrane	1
tertiary granule	1
ficolin-1-rich granule	1
cell junction	1

Protein interactions and networks

STRING

1946 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NFASC	CNTNAP1	P78357	998
NFASC	GLDN	Q6ZMI3	998
NFASC	ANK3	Q12955	993
NFASC	ANK2	Q01484	920
NFASC	CNTN1	Q12860	915
NFASC	SPTBN4	Q9H254	903
NFASC	ANK1	P16157	899
NFASC	EZR	P15311	767
NFASC	SCN8A	Q9UQD0	759
NFASC	KCNQ2	O43526	708
NFASC	PTPRZ1	P23471	702
NFASC	NRCAM	Q92823	684
NFASC	CNTNAP2	Q9UHC6	674
NFASC	PTPRB	P23467	673
NFASC	NRXN1	Q9ULB1	651

IntAct

13 interactions, top by confidence:

A	B	Type	Score
ABCD4	ABCD4	psi-mi:“MI:0914”(association)	0.640
NFASC	ABL1	psi-mi:“MI:0915”(physical association)	0.400
CRK	NFASC	psi-mi:“MI:0915”(physical association)	0.400
NFASC	FYN	psi-mi:“MI:0915”(physical association)	0.400
GRB2	NFASC	psi-mi:“MI:0915”(physical association)	0.400
NCK1	NFASC	psi-mi:“MI:0915”(physical association)	0.400
NFASC	NRCAM	psi-mi:“MI:0915”(physical association)	0.400
APP	ESYT2	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (25): NFASC (Affinity Capture-RNA), NFASC (Affinity Capture-MS), NFASC (Affinity Capture-MS), NFASC (Two-hybrid), NFASC (Two-hybrid), NFASC (Affinity Capture-RNA), NFASC (Affinity Capture-MS), NFASC (Co-fractionation), NFASC (Co-fractionation), NFASC (Co-fractionation), NFASC (Co-fractionation), NFASC (Co-fractionation), NFASC (Co-fractionation), NFASC (Co-fractionation), NFASC (Co-fractionation)

ESM2 similar proteins: A2A8L5, A4IFW2, A7MBJ4, B0V2N1, F1NWE3, O00533, O42414, O55005, O89026, O94856, O97394, P10586, P11627, P16621, P22063, P23468, P28685, P32004, P70232, P97685, P97686, Q02246, Q05695, Q13332, Q28902, Q2EY14, Q2EY15, Q2VWP7, Q2VWP9, Q3UH53, Q589G5, Q58EX2, Q61330, Q64487, Q64604, Q64605, Q6V4S5, Q7Z5N4, Q810U3, Q810U4

Diamond homologs: A0A087WV53, A2AAJ9, A2ASS6, A2RUH7, O75147, O94856, O94898, P05548, P52179, P54296, P97685, Q00872, Q23551, Q52KR2, Q5VST9, Q62234, Q80W87, Q810U3, Q8WX93, Q92626, A2CG49, F1M0Z1, O08775, O60229, O70468, O75962, O88599, P11799, P16419, P35918, P56741, P70402, P97924, Q05623, Q0KL02, Q13203, Q14324, Q14896, Q15746, Q5FW53

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
NFASC	“up-regulates quantity”	ANK2	relocalization
NFASC	“up-regulates quantity”	ANK3	relocalization
NFASC	“up-regulates quantity”	ANK1	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 12 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
FCGR3A-mediated phagocytosis	5	85.1×	5e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	5
Uncertain significance	208
Likely benign	67
Benign	21

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
2312256	NM_001005388.3(NFASC):c.2579_2580del (p.Leu860fs)	Pathogenic
4082143	NM_001005388.3(NFASC):c.2100C>A (p.Phe700Leu)	Pathogenic
4082144	NM_001160331.2(NFASC):c.2816del (p.Pro939fs)	Pathogenic
4082145	N124D	Pathogenic
4082146	NM_001005388.3(NFASC):c.2458T>C (p.Ser820Pro)	Pathogenic
4082147	NM_001005388.3(NFASC):c.3230T>C (p.Val1077Ala)	Pathogenic
620655	NM_001005388.3(NFASC):c.1076G>C (p.Arg359Pro)	Pathogenic
620656	NM_001160331.2(NFASC):c.2536C>T (p.Arg846Ter)	Pathogenic
620657	NM_001005388.3(NFASC):c.3365T>A (p.Val1122Glu)	Pathogenic
1030402	NM_001005388.3(NFASC):c.2398C>T (p.Arg800Ter)	Likely pathogenic
4535430	NM_001160331.2(NFASC):c.2616C>G (p.Tyr872Ter)	Likely pathogenic
4686068	NM_001160331.2(NFASC):c.2660G>A (p.Trp887Ter)	Likely pathogenic
976448	NM_001160331.2(NFASC):c.2677C>T (p.Gln893Ter)	Likely pathogenic
976449	NM_001005388.3(NFASC):c.3556G>T (p.Glu1186Ter)	Likely pathogenic

SpliceAI

6348 predictions. Top by Δscore:

Variant	Effect	Δscore
1:204828783:G:C	donor_loss	1.0000
1:204944220:CCACA:C	acceptor_loss	1.0000
1:204944223:CAG:C	acceptor_loss	1.0000
1:204944224:A:AG	acceptor_gain	1.0000
1:204944224:AG:A	acceptor_loss	1.0000
1:204944224:AGCT:A	acceptor_gain	1.0000
1:204944225:G:GA	acceptor_gain	1.0000
1:204944225:GC:G	acceptor_gain	1.0000
1:204944225:GCT:G	acceptor_gain	1.0000
1:204944225:GCTG:G	acceptor_gain	1.0000
1:204944225:GCTGA:G	acceptor_gain	1.0000
1:204944402:GGATC:G	donor_gain	1.0000
1:204944403:GATC:G	donor_gain	1.0000
1:204944403:GATCG:G	donor_gain	1.0000
1:204944407:G:GG	donor_gain	1.0000
1:204950532:A:AG	acceptor_gain	1.0000
1:204952007:GCA:G	acceptor_loss	1.0000
1:204952008:CA:C	acceptor_loss	1.0000
1:204952009:A:AC	acceptor_loss	1.0000
1:204952009:A:AG	acceptor_gain	1.0000
1:204952009:AGT:A	acceptor_gain	1.0000
1:204952010:G:GT	acceptor_gain	1.0000
1:204952010:GT:G	acceptor_gain	1.0000
1:204952010:GTG:G	acceptor_gain	1.0000
1:204952010:GTGAC:G	acceptor_gain	1.0000
1:204952114:CAGG:C	donor_loss	1.0000
1:204952117:G:GG	donor_gain	1.0000
1:204952118:T:A	donor_loss	1.0000
1:204954380:GTCTA:G	donor_gain	1.0000
1:204954385:G:GG	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000002563 (1:204896484 C>T), RS1000046872 (1:204943063 G>A), RS1000061129 (1:204858616 A>G,T), RS1000071058 (1:204932169 G>A,C,T), RS1000085741 (1:205013359 C>T), RS1000094416 (1:204888341 G>T), RS1000100190 (1:204943496 G>T), RS1000101889 (1:204848719 G>A), RS1000112188 (1:204890223 A>G), RS1000150738 (1:204883956 A>T), RS1000178191 (1:204891416 T>C), RS1000208412 (1:204835791 G>A), RS1000212078 (1:204984333 G>A,T), RS1000213892 (1:204976389 A>G), RS1000214103 (1:204839924 C>T)

Disease associations

OMIM: gene MIM:609145 | disease phenotypes: MIM:618356

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with central and peripheral motor dysfunction	Strong	Autosomal recessive

Mondo (2): neurodevelopmental disorder with central and peripheral motor dysfunction (MONDO:0032698), neuromuscular disease (MONDO:0019056)

Orphanet (1): Neuromuscular disease (Orphanet:68381)

HPO phenotypes

37 total (30 of 37 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000162	Glossoptosis
HP:0000175	Cleft palate
HP:0000237	Small anterior fontanelle
HP:0000252	Microcephaly
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000426	Prominent nasal bridge
HP:0000431	Wide nasal bridge
HP:0000718	Aggressive behavior
HP:0000739	Anxiety
HP:0000762	Decreased nerve conduction velocity
HP:0000878	11 pairs of ribs
HP:0001187	Hyperextensibility of the finger joints
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001272	Cerebellar atrophy
HP:0001276	Hypertonia
HP:0001310	Dysmetria
HP:0001336	Myoclonus
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0001558	Decreased fetal movement
HP:0002075	Dysdiadochokinesis
HP:0002080	Intention tremor
HP:0002093	Respiratory insufficiency

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST001713_24	Dental caries	3.000000e-06
GCST001713_4	Dental caries	3.000000e-06
GCST002337_79	Amyotrophic lateral sclerosis (sporadic)	8.000000e-06
GCST002595_3	Clozapine-induced agranulocytosis	9.000000e-06
GCST002875_72	Diisocyanate-induced asthma	1.000000e-06
GCST004599_261	Mean platelet volume	1.000000e-28
GCST006396_2	Disrupted circadian rhythm (low relative amplitude of rest-activity cycles)	3.000000e-09
GCST006585_2733	Blood protein levels	8.000000e-37
GCST006922_4	Regular attendance at a religious group	3.000000e-08
GCST007325_304	General risk tolerance (MTAG)	6.000000e-15
GCST010994_2	High myopia	3.000000e-08
GCST90000047_20	Age at first sexual intercourse	2.000000e-09
GCST90002395_550	Mean platelet volume	3.000000e-58
GCST90002402_260	Platelet count	4.000000e-14

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0006995	response to diisocyanate
EFO:0009592	social interaction measurement
EFO:0008579	risk-taking behaviour
EFO:0009749	age at first sexual intercourse measurement
EFO:0004309	platelet count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009468	Neuromuscular Diseases	C10.668

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression, increases methylation	7
Aflatoxin B1	decreases expression, decreases methylation	4
bisphenol A	affects cotreatment, increases methylation, increases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
methyleugenol	decreases expression	1
propionaldehyde	increases expression	1
trichostatin A	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
nickel sulfate	decreases expression	1
pentanal	increases expression	1
CGP 52608	increases reaction, affects binding	1
rofecoxib	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, increases expression, affects cotreatment	1
quinocetone	increases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Temozolomide	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	increases abundance, decreases expression	1
Aldehydes	increases expression	1
Arsenic	affects methylation	1
Calcitriol	increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00331656	PHASE4	UNKNOWN	Comparative Study of Non-Invasive Mask Ventilation vs Cuirass Ventilation in Patients With Acute Respiratory Failure.
NCT00994552	PHASE4	UNKNOWN	Comparison of Pressure Support and Pressure Control Ventilation in Chronic Respiratory Failure
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00942227	PHASE3	COMPLETED	The Value of Traction in Treatment of Lumbar Radiculopathy
NCT00979108	PHASE3	COMPLETED	The Value of Traction in the Treatment of Cervical Radiculopathy
NCT01826487	PHASE3	COMPLETED	Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)
NCT02090959	PHASE3	TERMINATED	An Extension Study of Ataluren (PTC124) in Participants With Nonsense Mutation Dystrophinopathy
NCT02436096	PHASE3	COMPLETED	A Study to Evaluate eFFIcacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With fibRoMyalgia
NCT02829814	PHASE3	TERMINATED	Repeat of: A Study to Evaluate Efficacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With Fibromyalgia
NCT03179631	PHASE3	COMPLETED	Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy
NCT05126758	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Deramiocel (CAP-1002) in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT05156320	PHASE3	COMPLETED	Efficacy and Safety of Apitegromab in Patients With Later-Onset Spinal Muscular Atrophy Treated With Nusinersen or Risdiplam
NCT05337553	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy and Safety of Taldefgrobep Alfa in Participants With Spinal Muscular Atrophy
NCT05626855	PHASE3	ACTIVE_NOT_RECRUITING	Long-Term Safety & Efficacy of Apitegromab in Patients With SMA Who Completed Previous Trials of Apitegromab
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT01074359	PHASE2	TERMINATED	Safety and Efficacy Study of A0001 in Patients With the A3243G Mitochondrial DNA Point Mutation
NCT01371149	PHASE2	COMPLETED	Patient -Ventilator Interaction in Chronic Respiratory Failure
NCT02022072	PHASE2	TERMINATED	Evaluation of Vital Capacity
NCT03127514	PHASE2	COMPLETED	AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT03406780	PHASE2	COMPLETED	A Study of CAP-1002 in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT03921528	PHASE2	COMPLETED	An Active Treatment Study of SRK-015 in Patients With Type 2 or Type 3 Spinal Muscular Atrophy
NCT05479981	PHASE2	COMPLETED	Extension of AOC 1001-CS1 (MARINA) Study in Adult Myotonic Dystrophy Type 1 (DM1) Patients
NCT06339580	PHASE2	RECRUITING	Assessment of Volume-targeted Ventilation in Patients With Neuromuscular Disease
NCT07071935	PHASE2	NOT_YET_RECRUITING	A Clinical Trial of Early Ventilation in Amyotrophic Lateral Sclerosis (EVENT ALS)
NCT07287189	PHASE2	RECRUITING	Phase 2 Study of SAT-3247 in Pediatric Ambulatory Patients
NCT00252252	PHASE1	COMPLETED	AutoVPAP Versus VPAP; Assessment of Sleep and Ventilation
NCT01560741	PHASE1	UNKNOWN	Telemedicine and Ventilator Titration in Chronic Respiratory Patients Initiating Non-invasive Ventilation
NCT01621984	PHASE1	COMPLETED	Therapeutic Riding and Neuromuscular Disease
NCT01758510	PHASE1	COMPLETED	Safety Study of HLA-haplo Matched Allogenic Bone Marrow Derived Stem Cell Treatment in Amyotrophic Lateral Sclerosis
NCT03440034	PHASE1	COMPLETED	Study of Pioglitazone in Sporadic Inclusion Body Myositis
NCT05730842	PHASE1	COMPLETED	Absorption, Metabolism, Excretion and Absolute Bioavailability of EDG-5506 in Healthy Volunteers
NCT03272802	PHASE2/PHASE3	UNKNOWN	Treatment Effect of Edaravone in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00860951	PHASE1/PHASE2	COMPLETED	P300 Brain Computer Interface Keyboard to Operate Assistive Technology
NCT02362425	PHASE1/PHASE2	COMPLETED	Antioxidant Therapy in RYR1-Related Congenital Myopathy
NCT00001201	Not specified	COMPLETED	Evaluation of Neuromuscular Disease
NCT00002044	Not specified	COMPLETED	A Pilot Study To Evaluate the Effect of Retrovir (Zidovudine: AZT) in the Treatment of Human Immunodeficiency Virus (HIV) Associated Dementia and Neuromuscular Diseases
NCT00004553	Not specified	COMPLETED	Electromyography to Diagnose Neuromuscular Disorders
NCT00015470	Not specified	COMPLETED	Diagnostic Evaluation of Patients With Neuromuscular Disease
NCT00017745	Not specified	COMPLETED	Phenotype/Genotype Correlations in Neuromuscular Disorders
NCT00695591	Not specified	COMPLETED	Home Sleep Testing in Neuromuscular Disease Patients