GAN

Summary

GAN (gigaxonin, HGNC:4137) is a protein-coding gene on chromosome 16q23.2, encoding Gigaxonin (Q9H2C0). Probable cytoskeletal component that directly or indirectly plays an important role in neurofilament architecture.

This gene encodes a member of the cytoskeletal BTB/kelch (Broad-Complex, Tramtrack and Bric a brac) repeat family. The encoded protein plays a role in neurofilament architecture and is involved in mediating the ubiquitination and degradation of some proteins. Defects in this gene are a cause of giant axonal neuropathy (GAN).

Source: NCBI Gene 8139 — RefSeq curated summary.

At a glance

• Gene–disease (curated): giant axonal neuropathy 1 (Definitive, ClinGen)
• GWAS associations: 8
• Clinical variants (ClinVar): 884 total — 39 pathogenic, 19 likely-pathogenic
• Phenotypes (HPO): 51
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_022041

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4137
Approved symbol	GAN
Name	gigaxonin
Location	16q23.2
Locus type	gene with protein product
Status	Approved
Aliases	GAN1, KLHL16, GIG
Ensembl gene	ENSG00000261609
Ensembl biotype	protein_coding
OMIM	605379
Entrez	8139

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 3 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000567335, ENST00000648349, ENST00000648994, ENST00000650388, ENST00000674788, ENST00000718305, ENST00000880995

RefSeq mRNA: 2 — MANE Select: NM_022041 NM_001377486, NM_022041

CCDS: CCDS10935

Canonical transcript exons

ENST00000648994 — 11 exons

Exon	Start	End
ENSE00000874981	81351583	81351697
ENSE00000874982	81354405	81354755
ENSE00001137443	81377219	81377328
ENSE00001137447	81365350	81365478
ENSE00001137459	81363794	81363943
ENSE00001137465	81362499	81362611
ENSE00001137469	81357810	81357931
ENSE00001137478	81356785	81357002
ENSE00001321335	81364974	81365110
ENSE00003833329	81377415	81390809
ENSE00003838276	81314962	81315280

Expression profiles

Bgee: expression breadth ubiquitous, 252 present calls, max score 98.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.5787 / max 100.3925, expressed in 1720 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155148	10.5787	1720

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper leg skin	UBERON:0004262	98.84	gold quality
skin of hip	UBERON:0001554	96.12	gold quality
penis	UBERON:0000989	94.59	gold quality
mammalian vulva	UBERON:0000997	92.88	gold quality
nipple	UBERON:0002030	92.39	gold quality
gingival epithelium	UBERON:0001949	91.04	gold quality
gingiva	UBERON:0001828	90.44	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.78	gold quality
zone of skin	UBERON:0000014	86.01	gold quality
skin of abdomen	UBERON:0001416	85.62	gold quality
corpus callosum	UBERON:0002336	85.55	gold quality
skin of leg	UBERON:0001511	85.12	gold quality
esophagus squamous epithelium	UBERON:0006920	84.97	gold quality
oral cavity	UBERON:0000167	83.90	gold quality
buccal mucosa cell	CL:0002336	83.87	silver quality
upper arm skin	UBERON:0004263	83.52	gold quality
amniotic fluid	UBERON:0000173	83.06	gold quality
epithelium of nasopharynx	UBERON:0001951	81.44	gold quality
substantia nigra pars compacta	UBERON:0001965	81.04	gold quality
palpebral conjunctiva	UBERON:0001812	80.69	gold quality
substantia nigra pars reticulata	UBERON:0001966	80.38	gold quality
middle temporal gyrus	UBERON:0002771	80.37	gold quality
colonic epithelium	UBERON:0000397	80.30	gold quality
ventral tegmental area	UBERON:0002691	80.16	gold quality
medial globus pallidus	UBERON:0002477	80.09	gold quality
Brodmann (1909) area 23	UBERON:0013554	79.95	gold quality
lower esophagus mucosa	UBERON:0035834	79.95	gold quality
globus pallidus	UBERON:0001875	79.60	gold quality
epithelium of esophagus	UBERON:0001976	79.31	gold quality
entorhinal cortex	UBERON:0002728	79.31	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 23)

• Gigaxonin interacts with tubulin folding cofactor B and controls its degradation through the ubiquitin-proteasome pathway. (PMID:16303566)
• Ubiquitin-proteasome system shown to be responsible for neurodegeneration occurring in GAN-null neurons and plays crucial roles in cytoskeletal functions and dynamics. (PMID:17256086)
• 3 new mutants were found in patients with giant axonal neuropathy: an intronic mutation near the splice donor site of intron 2 & a missense mutation in exon 3 (I182N), & 2 identical deletion alleles. (PMID:17331252)
• Five families with GAN for mutations in the Gigaxonin gene and mutations were found in four families; three families had homozygous mutations, one had two compound heterozygous mutations and one family had no mutation identified. (PMID:17578852)
• gigaxonin mutations impede this ubiquitin degradation process leading to accumulation of microtubule associated proteins and there by impairing cellular functions (PMID:17587580)
• a functional important part of the gigaxonin protein is altered by the AluYa5 insertion and causes giant axonal neuropathy [case report] (PMID:18595793)
• Study shows that the gigaxonin E3 ligase subunit is normally expressed at a very low level and that various missense and nonsense mutations scattered across the entire GAN gene produce highly unstable protein products. (PMID:19168853)
• No GAN variant is identified in DNA obtained from well-characterized cases of human neuronal intermediate filament inclusion disease (frontotemporal dementia). (PMID:19782434)
• A novel missense mutation in four siblings born to consanguineous parents of Arab origin with clinical and molecular features compatible with giant axonal neuropathy. (PMID:23332420)
• gigaxonin is a major factor in the degradation of cytoskeletal intermediate filaments (PMID:23585478)
• This study showed that The instability of Gigaxonin causes Giant Axonal Neuropathy. (PMID:24758703)
• The disease is caused by GAN gene mutations on chromosome 16q24.1. To determine clinical and genetic results in Turkish patients with GAN. (PMID:25533284)
• a proteomic screen to identify the normal binding partners of GIG, is reported. (PMID:26460568)
• Our protocol showed high specificity and sensitivity for homozygosity detection and facilitated the identification of novel mutations in GAN, GBA2, and ZFYVE26 in four families affected by hereditary spastic paraplegia or Charcot-Marie-Tooth disease (PMID:26492578)
• We believe that molecular and functional investigation of gigaxonin mutations including the exon 8 polymorphism could lead to an improved understanding of the relationship between GAN and cancer (PMID:27023907)
• A novel sequence alteration in the gene GAN, c.103G > T, was identified as most likely the underlying cause for a sensory-motor axonal neuropathy in a large consanguineous family presenting as Charcot-Marie-Tooth disease type 2. (PMID:27852232)
• Study data clearly show that upon overexpression, KLHL16 degrades several keratins including K6, K16, and K17, associated with wound healing, migration, and inflammation, states that are known to require extensive keratin remodeling. (PMID:29481904)
• gigaxonin as a key E3 ligase that positively controls the initiation of Shh transduction, and reveal the causal role of Shh dysfunction in motor deficits, thus highlighting the developmental origin of giant axonal neuropathy. (PMID:31503551)
• Giant axonal neuropathy: a multicenter retrospective study with genotypic spectrum expansion. (PMID:31655922)
• Identification of novel pathogenic copy number variations in Charcot-Marie-Tooth disease. (PMID:31852984)
• Giant axonal neuropathy with novel GAN pathogenic variant in a patient of consanguineous origin from Poonch Jammu and Kashmir-India. (PMID:33528728)
• Two novel pathogenic mutations of GAN gene identified in a chinese family with giant axonal neuropathy: a case report. (PMID:35764747)
• Gigaxonin is required for intermediate filament transport. (PMID:37043392)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	GAN	ENSDARG00000100875
mus_musculus	Gan	ENSMUSG00000052557
rattus_norvegicus	Gan	ENSRNOG00000012671

Paralogs (54): KLHL13 (ENSG00000003096), KLHL20 (ENSG00000076321), KEAP1 (ENSG00000079999), KLHL42 (ENSG00000087448), KLHL22 (ENSG00000099910), KLHL4 (ENSG00000102271), KLHL2 (ENSG00000109466), KLHL5 (ENSG00000109790), BACH2 (ENSG00000112182), KLHL18 (ENSG00000114648), KLHL24 (ENSG00000114796), IVNS1ABP (ENSG00000116679), KLHL12 (ENSG00000117153), KLHL29 (ENSG00000119771), KBTBD7 (ENSG00000120696), KLHL7 (ENSG00000122550), KLHL31 (ENSG00000124743), KLHDC7B (ENSG00000130487), KLHL36 (ENSG00000135686), KLHL8 (ENSG00000145332), KLHL3 (ENSG00000146021), KLHL35 (ENSG00000149243), KLHL1 (ENSG00000150361), BACH1 (ENSG00000156273), KLHL40 (ENSG00000157119), KLHL10 (ENSG00000161594), KLHL21 (ENSG00000162413), KLHDC8A (ENSG00000162873), KBTBD8 (ENSG00000163376), KBTBD6 (ENSG00000165572), KLHL26 (ENSG00000167487), KLHL30 (ENSG00000168427), KBTBD2 (ENSG00000170852), KLHL6 (ENSG00000172578), KLHL15 (ENSG00000174010), KLHL38 (ENSG00000175946), KBTBD11 (ENSG00000176595), KLHDC7A (ENSG00000179023), KLHL28 (ENSG00000179454), KBTBD3 (ENSG00000182359)

Protein

Protein identifiers

Gigaxonin — Q9H2C0 (reviewed: Q9H2C0)

Alternative names: Kelch-like protein 16

All UniProt accessions (4): A0A0S2Z4W2, A0A0S2Z5G5, A0A3B3ITY2, Q9H2C0

UniProt curated annotations — full annotation on UniProt →

Function. Probable cytoskeletal component that directly or indirectly plays an important role in neurofilament architecture. May act as a substrate-specific adapter of an E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Controls degradation of TBCB. Controls degradation of MAP1B and MAP1S, and is critical for neuronal maintenance and survival.

Subunit / interactions. Interacts with TBCB. Interacts with CUL3. Part of a complex that contains CUL3, RBX1 and GAN. Interacts (via BTB domain) with UBA1. Interacts (via Kelch domains) with MAP1B (via C-terminus) and MAP1S (via C-terminus).

Subcellular location. Cytoplasm. Cytoskeleton.

Tissue specificity. Expressed in brain, heart and muscle.

Post-translational modifications. Ubiquitinated by E3 ubiquitin ligase complex formed by CUL3 and RBX1 and probably targeted for proteasome-independent degradation.

Disease relevance. Giant axonal neuropathy 1, autosomal recessive (GAN1) [MIM:256850] A severe autosomal recessive sensorimotor neuropathy affecting both the peripheral nerves and the central nervous system. Axonal loss and the presence of giant axonal swellings filled with neurofilaments on nerve biopsies are the hallmarks of this neurodegenerative disorder. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (2): NP_001364415, NP_071324* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR006652	Kelch_1	Repeat
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR011705	BACK	Domain
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily
IPR017096	BTB-kelch_protein	Family
IPR030579	KLHL16_BACK	Domain
IPR047070	KLHL16_BTB_POZ	Domain

Pfam: PF00651, PF07707, PF24681

UniProt features (50 total): sequence variant 21, helix 14, repeat 6, strand 3, turn 3, domain 2, chain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2PPI	X-RAY DIFFRACTION	2.4
3HVE	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H2C0-F1	89.93	0.70

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-8951664	Neddylation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 267 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, ACTACCT_MIR196A_MIR196B, CCAWYNNGAAR_UNKNOWN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, KENNY_CTNNB1_TARGETS_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, HNF1_Q6, AGGCACT_MIR5153P, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, MYB_Q3, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, HNF1_01, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_TURQUOISE_UP

GO Biological Process (3): cytoskeleton organization (GO:0007010), protein ubiquitination (GO:0016567), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161)

GO Molecular Function (2): ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), cytoskeleton (GO:0005856), Cul3-RING ubiquitin ligase complex (GO:0031463)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Post-translational protein modification	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
organelle organization	1
protein modification by small protein conjugation	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
enzyme-substrate adaptor activity	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
intracellular membraneless organelle	1
cullin-RING ubiquitin ligase complex	1

Protein interactions and networks

STRING

1011 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GAN	MAP1B	P46821	981
GAN	UBA1	P22314	830
GAN	CUL3	Q13618	785
GAN	TBCB	Q99426	766
GAN	DNAL1	Q4LDG9	764
GAN	VIM	P08670	693
GAN	MAP1S	Q66K74	676
GAN	DCAF8	Q5TAQ9	644
GAN	RBX1	P62877	560
GAN	GFAP	P14136	504
GAN	NEFL	P07196	458
GAN	INA	Q16352	431
GAN	RNF216	Q9NWF9	430
GAN	FMR1	Q06787	424
GAN	SACS	Q9NZJ4	413
GAN	OTUD4	Q01804	413

IntAct

100 interactions, top by confidence:

A	B	Type	Score
VIM	NEFL	psi-mi:“MI:0914”(association)	0.840
NEFM	NEFL	psi-mi:“MI:0914”(association)	0.800
CCDC22	VPS26C	psi-mi:“MI:0914”(association)	0.790
KRT31	HGS	psi-mi:“MI:0914”(association)	0.780
NUDCD3	GAN	psi-mi:“MI:0915”(physical association)	0.740
H2AX	PPM1G	psi-mi:“MI:0914”(association)	0.730
SFN	GAN	psi-mi:“MI:0915”(physical association)	0.640
INPP5K	GART	psi-mi:“MI:0914”(association)	0.640
CCDC120	AIP	psi-mi:“MI:0914”(association)	0.640
GAN	PRKN	psi-mi:“MI:0915”(physical association)	0.560
GAN	VHL	psi-mi:“MI:0915”(physical association)	0.560
GAN	MAP1B	psi-mi:“MI:0915”(physical association)	0.560
MAP1B	GAN	psi-mi:“MI:0915”(physical association)	0.560
Uba1	GAN	psi-mi:“MI:0915”(physical association)	0.540
GAN	Uba1	psi-mi:“MI:0407”(direct interaction)	0.540
CUL3	RHOBTB1	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
NEFM	EVI5	psi-mi:“MI:0914”(association)	0.530
TAF8	TAF4	psi-mi:“MI:0914”(association)	0.530
PAK5	ARHGEF11	psi-mi:“MI:0914”(association)	0.530
GPSM3	ATE1	psi-mi:“MI:0914”(association)	0.530

BioGRID (303): GAN (Affinity Capture-MS), GAN (Affinity Capture-Western), GAN (Biochemical Activity), GAN (Affinity Capture-MS), GAN (Affinity Capture-MS), KIF11 (Affinity Capture-MS), HSPA1A (Affinity Capture-MS), HSPA1L (Affinity Capture-MS), PRMT5 (Affinity Capture-MS), TUBB (Affinity Capture-MS), TUBB4B (Affinity Capture-MS), WDR77 (Affinity Capture-MS), TUBB2B (Affinity Capture-MS), HSPA6 (Affinity Capture-MS), HSPA8 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B8YAB1, B1H285, B3DIV9, E9QIN8, E9QJ30, F1QEG2, O88879, Q08CL3, Q08CY1, Q0D2A9, Q13939, Q28068, Q3UQV5, Q3ZCT8, Q503R4, Q5F3N5, Q5R4S6, Q5R663, Q5RG82, Q5XHZ6, Q5XI58, Q5ZI33, Q69ZK5, Q6DFF7, Q6DFU2, Q6Q7X9, Q6V595, Q7ZVQ8, Q86V97, Q8BHI4, Q8BUL5, Q8BWA5, Q8CA72, Q8CDE2, Q8CE33, Q8IXQ5, Q8NAB2, Q8NFY9, Q8R179, Q8WVZ9

Diamond homologs: A0A0A6YY25, B2RXH4, E0CZ16, E1B932, E7F6F9, F1LZ52, F1LZF0, F1MBP6, O88282, O93567, O95198, P10074, P17789, P42282, P42283, P42284, Q01295, Q1H9T6, Q24174, Q24206, Q3B7M1, Q52KG4, Q53G59, Q53HC5, Q5R633, Q5REP9, Q5U374, Q66HD2, Q6NRH0, Q7KQZ4, Q7KRI2, Q867Z4, Q86B87, Q8BGY4, Q8BZM0, Q8CA72, Q8IN81, Q8JZP3, Q8K0L9, Q8N143

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
GAN	“up-regulates activity”	CUL3	binding
GAN	“down-regulates quantity”	ATG16L1	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 115 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	5	46.4×	1e-05
Activation of BH3-only proteins	5	30.3×	7e-05
Intrinsic Pathway for Apoptosis	5	17.9×	4e-04
Formation of the cornified envelope	10	10.7×	1e-05
Apoptosis	5	10.2×	4e-03
Programmed Cell Death	5	8.9×	7e-03
Keratinization	10	6.8×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
intermediate filament organization	15	33.1×	2e-16
morphogenesis of an epithelium	8	25.2×	3e-07
epithelial cell differentiation	7	11.3×	8e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	39
Likely pathogenic	19
Uncertain significance	443
Likely benign	273
Benign	59

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069095	NM_022041.4(GAN):c.902dup (p.Pro301_Asn302insTer)	Pathogenic
1069107	NM_022041.4(GAN):c.1485C>A (p.Tyr495Ter)	Pathogenic
1075713	NM_022041.4(GAN):c.384del (p.Gly127_Cys128insTer)	Pathogenic
1076942	NM_022041.4(GAN):c.993del (p.Phe331fs)	Pathogenic
1382301	NM_022041.4(GAN):c.502G>T (p.Glu168Ter)	Pathogenic
1438802	NM_022041.4(GAN):c.301dup (p.Thr101fs)	Pathogenic
1451193	NM_022041.4(GAN):c.307C>T (p.Gln103Ter)	Pathogenic
1795359	NM_022041.4(GAN):c.1112_1124delinsGA (p.Glu371fs)	Pathogenic
1996143	NM_022041.4(GAN):c.1182C>A (p.Tyr394Ter)	Pathogenic
2041538	NM_022041.4(GAN):c.1191T>A (p.Tyr397Ter)	Pathogenic
2431042	NM_022041.4(GAN):c.215A>T (p.Lys72Met)	Pathogenic
2431043	NM_022041.4(GAN):c.1387G>A (p.Ala463Thr)	Pathogenic
245920	NM_022041.4(GAN):c.633+2T>C	Pathogenic
2498221	NM_022041.4(GAN):c.861dup (p.Pro288fs)	Pathogenic
2759652	NM_022041.4(GAN):c.779_780del (p.Glu260fs)	Pathogenic
2808332	NM_022041.4(GAN):c.206_213dup (p.Lys72fs)	Pathogenic
2839021	NM_022041.4(GAN):c.582T>A (p.Tyr194Ter)	Pathogenic
2857348	NM_022041.4(GAN):c.384C>A (p.Cys128Ter)	Pathogenic
2871112	NM_022041.4(GAN):c.118G>T (p.Glu40Ter)	Pathogenic
2991358	NM_022041.4(GAN):c.1182C>G (p.Tyr394Ter)	Pathogenic
3243433	NC_000016.9:g.(?81348719)(81411201_?)del	Pathogenic
3243434	NC_000016.9:g.(?81348719)(81348905_?)del	Pathogenic
3243435	NC_000016.9:g.(?81385168)(81391556_?)del	Pathogenic
3701765	NM_022041.4(GAN):c.1494del (p.Glu498fs)	Pathogenic
3729264	NM_022041.4(GAN):c.737_738del (p.Lys246fs)	Pathogenic
3775527	NM_022041.4(GAN):c.625_626insCT (p.Ile209fs)	Pathogenic
3776270	NM_022041.4(GAN):c.1506del (p.Arg501_Trp502insTer)	Pathogenic
4279051	NM_022041.4(GAN):c.1361delinsAA (p.Leu454fs)	Pathogenic
4291901	NM_022041.4(GAN):c.605G>A (p.Trp202Ter)	Pathogenic
465385	NM_022041.4(GAN):c.1157del (p.Lys386fs)	Pathogenic

SpliceAI

2096 predictions. Top by Δscore:

Variant	Effect	Δscore
16:81351581:A:AG	acceptor_gain	1.0000
16:81351582:G:GG	acceptor_gain	1.0000
16:81354404:GATCA:G	acceptor_gain	1.0000
16:81354660:G:GT	donor_gain	1.0000
16:81354701:A:G	donor_gain	1.0000
16:81354751:GAAAG:G	donor_gain	1.0000
16:81354752:AAAG:A	donor_loss	1.0000
16:81354754:AGGTA:A	donor_loss	1.0000
16:81354756:G:T	donor_loss	1.0000
16:81356780:T:A	acceptor_gain	1.0000
16:81356781:GCA:G	acceptor_loss	1.0000
16:81356782:CAG:C	acceptor_loss	1.0000
16:81356783:A:AG	acceptor_gain	1.0000
16:81356783:A:AT	acceptor_loss	1.0000
16:81356784:G:GA	acceptor_gain	1.0000
16:81356784:GGTC:G	acceptor_gain	1.0000
16:81356784:GGTCC:G	acceptor_gain	1.0000
16:81356998:AGAGT:A	donor_gain	1.0000
16:81356999:GAGT:G	donor_gain	1.0000
16:81356999:GAGTG:G	donor_gain	1.0000
16:81357000:AGT:A	donor_gain	1.0000
16:81357001:GT:G	donor_gain	1.0000
16:81357001:GTG:G	donor_gain	1.0000
16:81357002:TG:T	donor_loss	1.0000
16:81357002:TGT:T	donor_gain	1.0000
16:81357003:G:GA	donor_loss	1.0000
16:81357003:G:GG	donor_gain	1.0000
16:81357004:T:G	donor_loss	1.0000
16:81357007:G:GG	donor_gain	1.0000
16:81362487:T:TA	acceptor_gain	1.0000

AlphaMissense

3928 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:81315267:A:C	S52R	1.000
16:81315269:C:A	S52R	1.000
16:81315269:C:G	S52R	1.000
16:81354447:G:C	A109P	1.000
16:81354485:C:G	C121W	1.000
16:81354524:T:G	C134W	1.000
16:81354726:T:A	W202R	1.000
16:81354726:T:C	W202R	1.000
16:81365079:T:A	W448R	1.000
16:81365079:T:C	W448R	1.000
16:81365110:G:T	R458M	1.000
16:81365397:G:A	G474E	1.000
16:81377220:T:A	W502R	1.000
16:81377220:T:C	W502R	1.000
16:81377314:G:A	G533E	1.000
16:81377320:T:C	L535P	1.000
16:81377462:T:A	W554R	1.000
16:81377462:T:C	W554R	1.000
16:81354427:T:A	I102N	0.999
16:81354439:T:A	V106D	0.999
16:81354444:G:C	A108P	0.999
16:81354448:C:A	A109D	0.999
16:81354454:T:C	L111P	0.999
16:81354457:T:C	L112P	0.999
16:81354460:T:C	L113P	0.999
16:81354472:T:A	L117H	0.999
16:81354483:T:C	C121R	0.999
16:81354484:G:A	C121Y	0.999
16:81354492:T:C	F124L	0.999
16:81354494:T:A	F124L	0.999

dbSNP variants (sampled 300 via entrez): RS1000012103 (16:81386809 G>A), RS1000036759 (16:81314932 C>A,G,T), RS1000046297 (16:81385974 C>G,T), RS1000085174 (16:81386694 C>T), RS1000086038 (16:81358477 C>T), RS1000087377 (16:81315030 G>C), RS1000104563 (16:81332101 C>A,T), RS1000108566 (16:81362785 C>A,T), RS1000114578 (16:81369556 A>G), RS1000166894 (16:81369285 A>G), RS1000212052 (16:81329016 A>C), RS1000223536 (16:81342923 G>A,C), RS1000230699 (16:81332545 C>A,T), RS1000272014 (16:81354900 A>G), RS1000280886 (16:81359161 G>C)

Disease associations

OMIM: gene MIM:605379 | disease phenotypes: MIM:256850, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
giant axonal neuropathy 1	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
giant axonal neuropathy 1	Definitive	AR

Mondo (5): giant axonal neuropathy 1 (MONDO:0009749), Charcot-Marie-Tooth disease (MONDO:0015626), giant axonal neuropathy (MONDO:0000128), peripheral neuropathy (MONDO:0005244), intellectual disability (MONDO:0001071)

Orphanet (3): Giant axonal neuropathy (Orphanet:643), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

51 total (30 of 51 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000256	Macrocephaly
HP:0000486	Strabismus
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0001249	Intellectual disability
HP:0001257	Spasticity
HP:0001258	Spastic paraplegia
HP:0001260	Dysarthria
HP:0001270	Motor delay
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001317	Abnormal cerebellum morphology
HP:0001347	Hyperreflexia
HP:0001382	Joint hypermobility
HP:0001761	Pes cavus
HP:0001762	Talipes equinovarus
HP:0001763	Pes planus
HP:0002013	Vomiting
HP:0002062	Abnormal pyramidal tract morphology
HP:0002212	Curly hair
HP:0002224	Woolly hair
HP:0002235	Pili canaliculi
HP:0002317	Unsteady gait
HP:0002460	Distal muscle weakness
HP:0002522	Areflexia of lower limbs
HP:0002527	Falls
HP:0002600	Hyporeflexia of lower limbs
HP:0002650	Scoliosis

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002619_1	Age-related cataracts	2.000000e-06
GCST003262_286	Post bronchodilator FEV1	1.000000e-06
GCST003262_320	Post bronchodilator FEV1	8.000000e-07
GCST003262_321	Post bronchodilator FEV1	9.000000e-07
GCST005958_20	Waist-to-hip ratio adjusted for BMI (age >50)	4.000000e-06
GCST005962_30	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	1.000000e-06
GCST008513_32	Health literacy	5.000000e-06
GCST90013411_5	Skin and soft tissue infections	6.000000e-08

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0010104	health literacy measurement
EFO:1001489	skin and soft tissue Staphylococcus aureus infection

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D056768	Giant Axonal Neuropathy	C10.500.300.490; C10.574.500.495.490; C10.668.829.325; C10.668.829.800.300.490; C16.131.666.300.490; C16.320.400.375.490
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	2
GSK-J4	increases expression	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, decreases reaction	1
perfluorooctanoic acid	increases expression	1
potassium chromate(VI)	increases expression	1
nickel sulfate	increases expression	1
resorcinol	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
jinfukang	decreases expression	1
Sunitinib	increases expression	1
Doxorubicin	decreases expression	1
Plant Oils	increases expression	1
Quercetin	increases expression	1
T-2 Toxin	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	increases expression	1
Valproic Acid	increases expression	1
Vanadates	decreases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	increases methylation	1
Okadaic Acid	increases expression	1
Copper Sulfate	increases expression	1
Particulate Matter	decreases expression	1

Cellosaurus cell lines

7 cell lines: 5 cancer cell line, 2 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_DX03	HAP1 GAN (-)	Cancer cell line	Male
CVCL_DX37	HAP1 GAN (-) SLC35A1 (-) 1	Cancer cell line	Male
CVCL_DX38	HAP1 GAN (-) SLC35A1 (-) 2	Cancer cell line	Male
CVCL_DX39	HAP1 GAN (-) SLC35A1 (-) 3	Cancer cell line	Male
CVCL_DX40	HAP1 GAN (-) SLC35A1 (-) 4	Cancer cell line	Male
CVCL_UD63	WG0321	Finite cell line	Male
CVCL_UD64	WG0791	Finite cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00380965	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Chemotherapy-Induced Neuropathy
NCT00487981	PHASE4	TERMINATED	Spinal Cord Stimulation for Painful Diabetic Neuropathy
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT01192113	PHASE4	COMPLETED	Safety and Efficacy of Mecobalamin Injection in Peripheral Neuropathies Patients (Study JGAZSY091109)
NCT01373983	PHASE4	COMPLETED	Intrathecal Bolus Doses of Ziconotide
NCT01458015	PHASE4	TERMINATED	Tapentadol Versus Oxycodone - a Mechanism-based Treatment Approach in Neuropathic Pain
NCT02074267	PHASE4	COMPLETED	Clinical Study for Assessment of the Efficacy of Gabapentin (Carbatin and Neurontin) in Patients With Neuropathy Pain
NCT02372149	PHASE4	UNKNOWN	IVIg for Demyelination in Diabetes Mellitus
NCT02670161	PHASE4	ENROLLING_BY_INVITATION	Quality Improvement and Practice Based Research in Neurology Using the EMR
NCT07022938	PHASE4	COMPLETED	Nutritional Supplement for Treating Chemotherapy Induced Neuropathy
NCT07025005	PHASE4	RECRUITING	Fenofibrate Role in the Prophylaxis From Peripheral Neuropathy Induced by Bortezomib, Lenalidomide and Dexamethasone (VRd) Protocol in the Treatment of Patients With Multiple Myeloma (MM)
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT00058071	PHASE3	COMPLETED	Amifostine in Treating Peripheral Neuropathy in Patients Who Have Received Chemotherapy for Cancer
NCT00125268	PHASE3	TERMINATED	Near Infrared Light for the Treatment of Painful Peripheral Neuropathy
NCT00195013	PHASE3	COMPLETED	Randomized Placebo-Controlled Trial of Glutamine for Breast Cancer Patients With Peripheral Neuropathy
NCT00232141	PHASE3	COMPLETED	Study of Pregabalin Versus Placebo in the Treatment of Nerve Pain Associated With HIV Neuropathy
NCT00264875	PHASE3	COMPLETED	Open Label Safety And Efficacy Study Of Pregabalin In Subjects With Nerve Pain Asociated With Human Immunodeficiency Virus (HIV) Neuropathy
NCT00369564	PHASE3	COMPLETED	Glutamic Acid in Reducing Nerve Damage Caused by Vincristine in Young Patients With Cancer
NCT00471445	PHASE3	COMPLETED	Topical Amitriptyline and Ketamine Cream in Treating Peripheral Neuropathy Caused by Chemotherapy in Cancer Patients
NCT00489411	PHASE3	COMPLETED	Duloxetine in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer
NCT00710554	PHASE3	COMPLETED	A Study of Sativex® for Pain Relief of Peripheral Neuropathic Pain, Associated With Allodynia
NCT00711880	PHASE3	COMPLETED	A Study of Sativex® for Relief of Peripheral Neuropathic Pain Associated With Allodynia.
NCT00713323	PHASE3	COMPLETED	A Study to Compare the Safety and Tolerability of Sativex® in Patients With Neuropathic Pain.
NCT00713817	PHASE3	COMPLETED	A Study to Determine the Maintenance of Effect After Long-term Treatment of Sativex® in Subjects With Neuropathic Pain
NCT00775645	PHASE3	COMPLETED	S0715: Acetyl-L-Carnitine in Preventing Neuropathy in Women With Stage I, II, or IIIA Breast Cancer Undergoing Chemo
NCT00872352	PHASE3	UNKNOWN	Evaluation of Bortezomib Induced Peripheral Neuropathy of Multiple Myeloma (MM) Patients
NCT00998738	PHASE3	TERMINATED	Calcium and Magnesium in Preventing Peripheral Neuropathy Caused by Ixabepilone in Patients With Breast Cancer
NCT01049217	PHASE3	TERMINATED	Pregabalin Versus Placebo In The Treatment Of Neuropathic Pain Associated With HIV Neuropathy
NCT01099449	PHASE3	COMPLETED	Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity in Patients With Colon Cancer or Rectal Cancer Receiving Oxaliplatin-Based Combination Chemotherapy
NCT01288937	PHASE3	TERMINATED	A Placebo Controlled, Randomized, Double Blind Trial of Milnacipran for the Treatment of Idiopathic Neuropathy Pain
NCT01492920	PHASE3	WITHDRAWN	Acetyl-L-Carnitine Hydrochloride in Preventing Peripheral Neuropathy in Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer Undergoing Chemotherapy
NCT01775449	PHASE3	COMPLETED	Prevention of Oxaliplatin-induced Neuropathic Pain by a Specific Diet
NCT02024191	PHASE3	UNKNOWN	The Role of Glutamine for Preventing Oxaliplatin-Induced Peripheral Neuropathy
NCT02217267	PHASE3	COMPLETED	Long Term Outcome After Serial Lidocaine Infusion in Peripheral Neuropathic Pain
NCT02294149	PHASE3	UNKNOWN	Vit D3 and Omega 3 in Chemo Induced Neuropathy
NCT02311907	PHASE3	COMPLETED	Glutathione in Preventing Peripheral Neuropathy Caused by Paclitaxel and Carboplatin in Patients With Ovarian Cancer, Fallopian Tube Cancer, and/or Primary Peritoneal Cancer
NCT06071936	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06071975	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT06071988	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06072573	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy