ATL3

Summary

ATL3 (atlastin GTPase 3, HGNC:24526) is a protein-coding gene on chromosome 11q13.1, encoding Atlastin-3 (Q6DD88). Atlastin-3 (ATL3) is a membrane-anchored GTPase that mediates the GTP-dependent fusion of endoplasmic reticulum (ER) membranes, maintaining the continuous ER network.

This gene encodes a member of a family of dynamin-like, integral membrane GTPases. The encoded protein is required for the proper formation of the network of interconnected tubules of the endoplasmic reticulum. Mutations in this gene may be associated with hereditary sensory neuropathy type IF. Alternatively spliced transcript variants that encode distinct isoforms have been described.

Source: NCBI Gene 25923 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neuropathy, hereditary sensory, type 1F (Strong, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 517 total — 2 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 39
• Druggable target: yes
• MANE Select transcript: NM_015459

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24526
Approved symbol	ATL3
Name	atlastin GTPase 3
Location	11q13.1
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP564J0863
Ensembl gene	ENSG00000184743
Ensembl biotype	protein_coding
OMIM	609369
Entrez	25923

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000398868, ENST00000535789, ENST00000538786, ENST00000540699, ENST00000955365

RefSeq mRNA: 2 — MANE Select: NM_015459 NM_001290048, NM_015459

CCDS: CCDS41663, CCDS73309

Canonical transcript exons

ENST00000398868 — 13 exons

Exon	Start	End
ENSE00001291691	63631040	63631471
ENSE00001305045	63636207	63636334
ENSE00001306614	63646507	63646563
ENSE00001316752	63658761	63658904
ENSE00001319139	63651936	63651986
ENSE00001325677	63644169	63644261
ENSE00001328306	63643357	63643495
ENSE00001535301	63671290	63671376
ENSE00002267761	63624087	63629405
ENSE00002468685	63635534	63635590
ENSE00002478444	63633026	63633097
ENSE00002521282	63652471	63652575
ENSE00003566817	63659038	63659252

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 99.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 54.1143 / max 1174.4692, expressed in 1819 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
120324	31.3271	1806
120327	8.6146	1690
120323	4.3643	1475
120328	3.7891	1471
120330	2.8879	1451
120329	2.3736	1341
120331	0.6969	421
120333	0.0285	3
120332	0.0249	3
120334	0.0074	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper arm skin	UBERON:0004263	99.28	gold quality
saphenous vein	UBERON:0007318	98.66	gold quality
layer of synovial tissue	UBERON:0007616	98.60	gold quality
synovial joint	UBERON:0002217	98.50	gold quality
calcaneal tendon	UBERON:0003701	98.17	gold quality
cauda epididymis	UBERON:0004360	98.16	gold quality
urethra	UBERON:0000057	97.96	gold quality
pericardium	UBERON:0002407	97.86	gold quality
skin of hip	UBERON:0001554	97.84	gold quality
vena cava	UBERON:0004087	97.79	gold quality
sperm	CL:0000019	97.27	gold quality
upper leg skin	UBERON:0004262	97.14	gold quality
penis	UBERON:0000989	97.09	gold quality
dorsal root ganglion	UBERON:0000044	97.02	gold quality
decidua	UBERON:0002450	97.01	gold quality
cartilage tissue	UBERON:0002418	96.94	gold quality
kidney epithelium	UBERON:0004819	96.94	gold quality
cardiac muscle of right atrium	UBERON:0003379	96.89	gold quality
mammalian vulva	UBERON:0000997	96.87	gold quality
nipple	UBERON:0002030	96.69	gold quality
parotid gland	UBERON:0001831	96.66	gold quality
tendon	UBERON:0000043	96.56	gold quality
superficial temporal artery	UBERON:0001614	96.55	gold quality
ileal mucosa	UBERON:0000331	96.50	gold quality
seminal vesicle	UBERON:0000998	96.48	gold quality
mammary duct	UBERON:0001765	96.40	gold quality
epithelium of mammary gland	UBERON:0003244	96.40	gold quality
trigeminal ganglion	UBERON:0001675	96.35	gold quality
caput epididymis	UBERON:0004358	96.11	gold quality
trabecular bone tissue	UBERON:0002483	95.99	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-75367	yes	249.46
E-ANND-3	yes	12.76

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

199 targeting ATL3, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872

Literature-anchored findings (GeneRIF, showing 12)

• A family of human GTPases, atlastin-2 and -3 that are closely related to atlastin-1 are described. (PMID:18270207)
• ATL3 is implicated in the structural organization of intracellular organelles, which may be critical to axonal survival. (PMID:24459106)
• These results suggest that the three ATLs have different capacities to mediate endoplasmic reticulum fusion, with ATL1 being the strongest and ATL3 being the weakest. (PMID:25773277)
• study reports that Sey1/Atl3 and Rtn4 localize to early Legionella-containing vacuoles (LCV) and are critical for pathogen vacuole formation; Sey1/Atl3-dependent ER remodeling contributes to LCV maturation and intracellular replication of L. pneumophila (PMID:28835546)
• the effects of ATL3 mutations on endoplasmic reticulum network organization go beyond a loss of fusion and shed light on neuropathies caused by atlastin defects. (PMID:29768202)
• the mitochondria in these cells display lowered motility, and the number of axonal mitochondria in neurons expressing disease-causing mutations in ATL3 is strongly decreased. These results underscore the functional interdependence of subcellular organelles in health and disease and show that disorders caused by ER-shaping defects are more complex than previously assumed. (PMID:30339187)
• ATL3 Y192C delays endoplasmic reticulum-export by reducing the number of endoplasmic reticulum exit sites, reduces autophagy, fragments the Golgi and causes malformation of the nucleus. In cultured primary neurons, ATL3 Y192C does not localize to the growing axon, resulting in axon growth deficits. (PMID:30666337)
• ATL3 functions as a receptor for endoplasmic reticulum (ER)-phagy, promoting tubular ER degradation upon starvation. ATL3 specifically binds to GABARAP, but not LC3, subfamily proteins via 2 GABARAP interaction motifs (GIMs). ATL3-GABARAP interaction is essential for ATL3 to function in ER-phagy. (PMID:30773365)
• Atlastin 2/3 regulate ER targeting of the ULK1 complex to initiate autophagy. (PMID:33988678)
• Rare mutations in ATL3, SPTLC2 and SCN9A explaining hereditary sensory neuropathy and congenital insensitivity to pain in a Brazilian cohort. (PMID:34090020)
• A novel nonsense variant in the ATL3 gene is associated with disturbed pain sensitivity, numbness of distal limbs and muscle weakness. (PMID:36856139)
• Human atlastin-3 is a constitutive ER membrane fusion catalyst. (PMID:37102997)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	atl3	ENSDARG00000004270
mus_musculus	Atl3	ENSMUSG00000024759
rattus_norvegicus	Atl3	ENSRNOG00000021203
caenorhabditis_elegans		WBGENE00021868

Paralogs (10): GBP3 (ENSG00000117226), GBP1 (ENSG00000117228), ATL2 (ENSG00000119787), RNF112 (ENSG00000128482), GBP5 (ENSG00000154451), GBP2 (ENSG00000162645), GBP4 (ENSG00000162654), GBP6 (ENSG00000183347), ATL1 (ENSG00000198513), GBP7 (ENSG00000213512)

Protein

Protein identifiers

Atlastin-3 — Q6DD88 (reviewed: Q6DD88)

All UniProt accessions (3): Q6DD88, F5GWF8, F5H6I7

UniProt curated annotations — full annotation on UniProt →

Function. Atlastin-3 (ATL3) is a membrane-anchored GTPase that mediates the GTP-dependent fusion of endoplasmic reticulum (ER) membranes, maintaining the continuous ER network. It facilitates the formation of three-way junctions where ER tubules intersect. Two atlastin-3 on neighboring ER tubules bind GTP and form loose homodimers through the GB1/RHD3-type G domains and 3HB regions. Upon GTP hydrolysis, the 3HB regions tighten, pulling the membranes together to drive their fusion. After fusion, the homodimer disassembles upon release of inorganic phosphate (Pi). Subsequently, GDP dissociates, resetting the monomers to a conformation ready for a new fusion cycle.

Subunit / interactions. Monomeric and homodimeric. The homodimer, transiently formed by two molecules on opposing membranes, is the active form mediating ER membrane fusion. Interacts with ZFYVE27; both proteins are involved in endoplasmic reticulum tubular network organization. Interacts with REEP5; both proteins are involved in endoplasmic reticulum tubular network organization.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in the central nervous system and in dorsal root ganglia neurons. Expressed in peripheral tissues (at protein level).

Disease relevance. Neuropathy, hereditary sensory, 1F (HSN1F) [MIM:615632] An autosomal dominant sensory neuropathy affecting the lower limbs. Distal sensory impairment becomes apparent during the second or third decade of life, resulting in painless ulceration of the feet with poor healing, which can progress to osteomyelitis, bone destruction, and amputation. There is no autonomic involvement, spasticity, or cognitive impairment. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The GB1/RHD3-type G domain mediates GTP-binding and hydrolysis as well as homodimerization. The two three-helix bundle (3HB) regions in the homodimer are loosely associated initially, but they tighten upon GTP hydrolysis, facilitating the fusion of membranes.

Similarity. Belongs to the TRAFAC class dynamin-like GTPase superfamily. GB1/RHD3 GTPase family. GB1 subfamily.

RefSeq proteins (2): NP_001276977, NP_056274* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003191	Guanylate-bd/ATL_C	Domain
IPR015894	Guanylate-bd_N	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR030386	G_GB1_RHD3_dom	Domain
IPR036543	Guanylate-bd_C_sf	Homologous_superfamily

Pfam: PF02263, PF02841

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (67 total): helix 16, binding site 12, strand 12, mutagenesis site 6, sequence conflict 6, topological domain 3, turn 3, transmembrane region 2, modified residue 2, region of interest 2, chain 1, sequence variant 1, domain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5VGR	X-RAY DIFFRACTION	2.1
6XJO	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6DD88-F1	87.30	0.61

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (12): 71; 72; 73; 74; 75; 109; 142; 213; 214; 272; 275; 70

Post-translational modifications (2): 391, 535

Mutagenesis-validated functional residues (6):

Position	Phenotype
70	loss of gtpase-dependent fusogenic activity.
73	changed endoplasmic reticulum tubular network membrane organization.
109	decreased gtpase activity.
213	changed endoplasmic reticulum tubular network membrane organization.
338	loss of gtpase-dependent fusogenic activity.
503	loss of gtpase-dependent fusogenic activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 257 (showing top): RRAGTTGT_UNKNOWN, HORIUCHI_WTAP_TARGETS_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, TGCACTT_MIR519C_MIR519B_MIR519A, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_MEMBRANE_FUSION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_VESICLE_MEDIATED_TRANSPORT, chr11q13, AACWWCAANK_UNKNOWN, GTGCCTT_MIR506, WEI_MYCN_TARGETS_WITH_E_BOX, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GOBP_ENDOPLASMIC_RETICULUM_TO_GOLGI_VESICLE_MEDIATED_TRANSPORT, GOBP_ORGANELLE_MEMBRANE_FUSION

GO Biological Process (5): endoplasmic reticulum organization (GO:0007029), endoplasmic reticulum membrane fusion (GO:0016320), protein homooligomerization (GO:0051260), endoplasmic reticulum tubular network membrane organization (GO:1990809), Golgi organization (GO:0007030)

GO Molecular Function (7): GTPase activity (GO:0003924), GTP binding (GO:0005525), identical protein binding (GO:0042802), GTPase-dependent fusogenic activity (GO:0140523), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (5): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), endoplasmic reticulum tubular network (GO:0071782), endoplasmic reticulum tubular network membrane (GO:0098826)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
organelle organization	2
endomembrane system organization	2
endoplasmic reticulum membrane organization	2
endoplasmic reticulum subcompartment	2
endoplasmic reticulum organization	1
organelle membrane fusion	1
protein complex oligomerization	1
endoplasmic reticulum tubular network organization	1
ribonucleoside triphosphate phosphatase activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein binding	1
GTPase activity	1
membrane fusion	1
fusogenic activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
cellular anatomical structure	1
endoplasmic reticulum membrane	1
endoplasmic reticulum tubular network	1

Protein interactions and networks

STRING

1170 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATL3	SPAST	Q9UBP0	965
ATL3	REEP1	Q9H902	950
ATL3	GABARAP	O95166	884
ATL3	GABARAPL2	P60520	869
ATL3	F5GZY7	F5GZY7	869
ATL3	RTN1	Q16799	860
ATL3	SPART	Q8N0X7	854
ATL3	SSNA1	O43805	821
ATL3	REEP5	Q00765	819
ATL3	CCPG1	Q9ULG6	817
ATL3	RETREG1	Q9H6L5	814
ATL3	SEC62	Q99442	800
ATL3	TEX264	Q9Y6I9	786
ATL3	RTN3	O95197	768
ATL3	CHMP1B	Q7LBR1	750

IntAct

120 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ZFYVE27	REEP5	psi-mi:“MI:0914”(association)	0.540
ATL3	ZFYVE27	psi-mi:“MI:0403”(colocalization)	0.540
ZFYVE27	ATL3	psi-mi:“MI:0915”(physical association)	0.540
ADGRG5	KLRG2	psi-mi:“MI:0914”(association)	0.530
MAS1	POTEF	psi-mi:“MI:0914”(association)	0.530
LPAR4	POTEF	psi-mi:“MI:0914”(association)	0.530
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
SLC2A12	METTL15	psi-mi:“MI:0914”(association)	0.530
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
GDE1	GAPDHS	psi-mi:“MI:0914”(association)	0.530
CNGA3	C2CD2L	psi-mi:“MI:0914”(association)	0.530
SLC5A5	SLC19A2	psi-mi:“MI:0914”(association)	0.530
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
ANAPC5	BUB1B	psi-mi:“MI:0914”(association)	0.530
SLC22A16	APBA3	psi-mi:“MI:0914”(association)	0.530
TMEM184A	SLC33A1	psi-mi:“MI:0914”(association)	0.530
sseJ	AGPS	psi-mi:“MI:0914”(association)	0.460
env	PGRMC1	psi-mi:“MI:0914”(association)	0.460

BioGRID (246): ATL3 (Affinity Capture-MS), ATL3 (Affinity Capture-MS), ATL3 (Affinity Capture-MS), ATL3 (Affinity Capture-MS), ASPH (Co-fractionation), ATL3 (Co-fractionation), ATL3 (Co-fractionation), ATL3 (Co-fractionation), ATL3 (Co-fractionation), ATL3 (Co-fractionation), ATL3 (Co-fractionation), ATL3 (Co-fractionation), ATL3 (Co-fractionation), ATL3 (Co-fractionation), ATL3 (Co-fractionation)

ESM2 similar proteins: A0PK00, A1L2R7, A3KNK1, A4FUY9, A6QPF8, A7MBC7, A8DZH4, D3ZWZ9, O14524, O95427, P86044, Q01685, Q0ZHH6, Q15629, Q1LY80, Q28CV2, Q3TA38, Q3ZBX1, Q4R8A8, Q5BJF2, Q5EAX9, Q5FWV6, Q5HZE5, Q5PQQ4, Q5R7Z3, Q5RDB4, Q5U4X7, Q5XI41, Q63ZG0, Q6AXF6, Q6DD88, Q6DE21, Q6DED0, Q6DHU1, Q6GQE1, Q6Q3F5, Q6R8G5, Q6R8G7, Q7ZX75, Q86X19

Diamond homologs: A0JN74, A6NK02, B1H278, I1YAP6, O00635, O19085, O70418, O77666, P0C8K8, P19474, P62603, Q08DF2, Q0PF16, Q0ZHH6, Q12899, Q14258, Q1ACD5, Q1ACD6, Q1ACD7, Q1ACD8, Q1XHT8, Q1XHU0, Q2T9Z0, Q2YEM8, Q2YEM9, Q2YEN0, Q2YEN2, Q3UWA4, Q3UWZ0, Q3ZEE5, Q495X7, Q587N6, Q587N7, Q58D72, Q5BK82, Q5BN31, Q5C8T6, Q5C8T8, Q5C8U1, Q5C8U3

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 143 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.

GO biological processes:

GO term	Partners	Fold	FDR
G protein-coupled receptor signaling pathway	16	4.7×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	268
Likely benign	177
Benign	32

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
932960	NM_015459.5(ATL3):c.1013C>G (p.Pro338Arg)	Pathogenic
97070	NM_015459.5(ATL3):c.575A>G (p.Tyr192Cys)	Pathogenic
152302	GRCh38/hg38 11q12.3-13.1(chr11:62893226-64335043)x1	Likely pathogenic
3895483	NM_015459.5(ATL3):c.1046_1066dup (p.Ala355_Ala356insGluAlaAsnAsnLeuAlaAla)	Likely pathogenic

SpliceAI

2073 predictions. Top by Δscore:

Variant	Effect	Δscore
11:63631311:T:TA	donor_gain	1.0000
11:63631467:CAAAC:C	acceptor_gain	1.0000
11:63631468:AAAC:A	acceptor_gain	1.0000
11:63631469:AAC:A	acceptor_gain	1.0000
11:63631470:AC:A	acceptor_gain	1.0000
11:63631471:CC:C	acceptor_gain	1.0000
11:63631472:C:CA	acceptor_loss	1.0000
11:63631472:C:CC	acceptor_gain	1.0000
11:63631472:C:T	acceptor_gain	1.0000
11:63631482:C:CT	acceptor_gain	1.0000
11:63633022:GTACC:G	donor_loss	1.0000
11:63633023:TA:T	donor_loss	1.0000
11:63633024:A:AC	donor_gain	1.0000
11:63633024:ACCTC:A	donor_loss	1.0000
11:63633025:C:CA	donor_loss	1.0000
11:63633025:C:CC	donor_gain	1.0000
11:63633025:CCT:C	donor_gain	1.0000
11:63633093:GTGGC:G	acceptor_gain	1.0000
11:63633094:TGGC:T	acceptor_gain	1.0000
11:63633096:GC:G	acceptor_gain	1.0000
11:63633097:CC:C	acceptor_gain	1.0000
11:63633098:C:CC	acceptor_gain	1.0000
11:63633099:T:C	acceptor_gain	1.0000
11:63633099:T:TC	acceptor_gain	1.0000
11:63633100:T:C	acceptor_gain	1.0000
11:63633100:T:TC	acceptor_gain	1.0000
11:63633101:T:C	acceptor_gain	1.0000
11:63633101:T:TC	acceptor_gain	1.0000
11:63636202:TTTA:T	donor_loss	1.0000
11:63636203:TTACC:T	donor_loss	1.0000

AlphaMissense

3563 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:63631368:A:G	M404T	1.000
11:63633070:C:G	A355P	1.000
11:63633085:C:G	A350P	1.000
11:63633090:G:T	A348D	1.000
11:63633091:C:G	A348P	1.000
11:63633097:C:G	A346P	1.000
11:63636318:G:C	F289L	1.000
11:63636318:G:T	F289L	1.000
11:63636320:A:G	F289L	1.000
11:63643436:G:C	F257L	1.000
11:63643436:G:T	F257L	1.000
11:63643438:A:G	F257L	1.000
11:63644237:A:G	W215R	1.000
11:63644237:A:T	W215R	1.000
11:63644239:T:A	D214V	1.000
11:63644242:C:A	R213I	1.000
11:63646541:A:G	L195P	1.000
11:63646544:C:G	R194P	1.000
11:63646547:C:T	G193D	1.000
11:63646551:A:G	Y192H	1.000
11:63646558:G:C	F189L	1.000
11:63646558:G:T	F189L	1.000
11:63646560:A:G	F189L	1.000
11:63646562:A:G	L188P	1.000
11:63651940:A:G	L186P	1.000
11:63651949:A:G	L183P	1.000
11:63651978:A:C	N173K	1.000
11:63651978:A:T	N173K	1.000
11:63652480:A:C	S167R	1.000
11:63652480:A:T	S167R	1.000

dbSNP variants (sampled 300 via entrez): RS1000002768 (11:63649697 A>C), RS1000054864 (11:63650131 T>C), RS1000253029 (11:63629503 G>A,T), RS1000314841 (11:63673276 G>A), RS1000399313 (11:63636326 C>G,T), RS1000431975 (11:63636556 T>G), RS1000499038 (11:63663892 C>T), RS1000638205 (11:63638565 C>G), RS1000736925 (11:63637670 A>G), RS1000748586 (11:63631960 C>A,T), RS1000866214 (11:63663510 T>C), RS1000909273 (11:63656692 C>A,T), RS1000918717 (11:63663980 A>C), RS1000943878 (11:63625537 T>C), RS1000967653 (11:63638758 C>T)

Disease associations

OMIM: gene MIM:609369 | disease phenotypes: MIM:615632, MIM:613287

GenCC curated gene-disease

Disease	Classification	Inheritance
neuropathy, hereditary sensory, type 1F	Strong	Autosomal dominant
hereditary sensory and autonomic neuropathy type 1	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
neuropathy, hereditary sensory, type 1F	Moderate	AD

Mondo (4): neuropathy, hereditary sensory, type 1F (MONDO:0014286), long QT syndrome (MONDO:0002442), Charcot-Marie-Tooth disease axonal type 2N (MONDO:0013212), hereditary sensory and autonomic neuropathy type 1 (MONDO:0018213)

Orphanet (2): Hereditary sensory and autonomic neuropathy type 1 (Orphanet:36386), Autosomal dominant Charcot-Marie-Tooth disease type 2N (Orphanet:228174)

HPO phenotypes

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

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000365	Hearing impairment
HP:0000962	Hyperkeratosis
HP:0001026	Penetrating foot ulcers
HP:0001058	Poor wound healing
HP:0001324	Muscle weakness
HP:0001822	Hallux valgus
HP:0002020	Gastroesophageal reflux
HP:0002141	Gait imbalance
HP:0002270	Abnormality of the autonomic nervous system
HP:0002460	Distal muscle weakness
HP:0002540	Inability to walk
HP:0002600	Hyporeflexia of lower limbs
HP:0002754	Osteomyelitis
HP:0002756	Pathologic fracture
HP:0002821	Neuropathic arthropathy
HP:0002936	Distal sensory impairment
HP:0003376	Steppage gait
HP:0003390	Sensory axonal neuropathy
HP:0003621	Juvenile onset
HP:0003693	Distal amyotrophy
HP:0006937	Impaired distal tactile sensation
HP:0007002	Motor axonal neuropathy
HP:0007021	Pain insensitivity
HP:0007078	Decreased amplitude of sensory action potentials
HP:0007328	Impaired pain sensation
HP:0007550	Hypohidrosis or hyperhidrosis
HP:0009027	Foot dorsiflexor weakness
HP:0009763	Limb pain
HP:0009771	Osteolytic defects of the phalanges of the hand

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
C567653	Charcot-Marie-Tooth Disease, Axonal, Type 2n (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067070 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.90	Kd	125.9	nM	CHEMBL5653589
6.90	ED50	125.9	nM	CHEMBL5653589
5.94	Kd	1145	nM	CHEMBL3752910
5.94	ED50	1145	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147904: Binding affinity to human ATL3 incubated for 45 mins by Kinobead based pull down assay	kd	0.1259	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147904: Binding affinity to human ATL3 incubated for 45 mins by Kinobead based pull down assay	kd	1.1452	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases methylation	7
Air Pollutants	affects cotreatment, increases abundance, increases expression, affects expression, decreases expression	3
bisphenol A	increases expression, affects cotreatment, decreases expression	2
sodium arsenite	decreases expression, increases abundance, increases expression, affects cotreatment	2
mercuric bromide	decreases expression, affects cotreatment	2
Acetaminophen	decreases expression	2
Arsenic	increases abundance, affects expression, affects cotreatment, decreases expression	2
Ozone	affects cotreatment, increases expression, increases abundance, affects expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	decreases expression	1
nickel sulfate	decreases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
bisphenol B	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Acrolein	affects cotreatment, increases expression, increases abundance	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5650946	Binding	Binding affinity to human ATL3 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

1 cell lines: 1 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_YU33	hTERT-ATL3 Y192C	Telomerase immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT06113055	PHASE2	UNKNOWN	Hereditary Sensory Neuropathy Serine Trial
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT01733407	PHASE1/PHASE2	COMPLETED	L-Serine Supplementation in Hereditary Sensory Neuropathy Type 1
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02425189	Not specified	COMPLETED	The Canadian National Long QT Syndrome Registry
NCT02439645	Not specified	TERMINATED	A Registry to Determine the Clinical and Genetic Risk Factors for Torsade De Pointes
NCT02439658	Not specified	UNKNOWN	Genetics of QT Prolongation With Antiarrhythmics
NCT02549664	Not specified	COMPLETED	Exercise in Genetic Cardiovascular Conditions
NCT02581241	Not specified	COMPLETED	Abnormal QT-Response to the Sudden Tachycardia Provoked by Standing in Individuals With Drug-induced Long QT Syndrome
NCT02680080	Not specified	COMPLETED	Effect of Grapefruit on QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome
NCT02775513	Not specified	UNKNOWN	Metabolism of Patients With Genetically Caused Cardiac Arrhythmia
NCT02814981	Not specified	UNKNOWN	Hydroxyzine and Risk of Prolongation of QT Interval
NCT02876380	Not specified	COMPLETED	Prospective Identification of Long QT Syndrome in Fetal Life
NCT03182777	Not specified	COMPLETED	Safety of Local Dental Anesthesia in Patients With Cardiac Channelopathies
NCT03544918	Not specified	COMPLETED	Prevalence of Congenital Long QT Syndrome and Acquired QT Prolongation in a Hospital Cohort