NPRL3

Summary

NPRL3 (NPR3 like, GATOR1 complex subunit, HGNC:14124) is a protein-coding gene on chromosome 16p13.3, encoding GATOR1 complex protein NPRL3 (Q12980). As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway. It is haploinsufficient (ClinGen: sufficient evidence).

Predicted to enable GTPase activator activity. Involved in cellular response to amino acid starvation and negative regulation of TORC1 signaling. Part of GATOR1 complex. Is active in lysosomal membrane. Implicated in familial focal epilepsy with variable foci 3.

Source: NCBI Gene 8131 — RefSeq curated summary.

At a glance

• Gene–disease (curated): focal epilepsy (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 58
• Clinical variants (ClinVar): 187 total — 42 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 51
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001077350

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14124
Approved symbol	NPRL3
Name	NPR3 like, GATOR1 complex subunit
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	CGTHBA, RMD11, NPR3, MARE, HS-40
Ensembl gene	ENSG00000103148
Ensembl biotype	protein_coding
OMIM	600928
Entrez	8131

Gene structure

Transcript identifiers

Ensembl transcripts: 76 — 67 protein_coding, 6 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000399953, ENST00000419636, ENST00000422814, ENST00000456528, ENST00000457916, ENST00000464069, ENST00000468260, ENST00000473674, ENST00000483663, ENST00000610509, ENST00000611875, ENST00000621703, ENST00000622194, ENST00000882130, ENST00000882131, ENST00000882132, ENST00000882133, ENST00000882134, ENST00000882135, ENST00000882136, ENST00000882137, ENST00000882138, ENST00000882139, ENST00000882140, ENST00000882141, ENST00000882142, ENST00000882143, ENST00000882144, ENST00000882145, ENST00000882146, ENST00000882147, ENST00000882148, ENST00000882149, ENST00000882150, ENST00000882151, ENST00000882152, ENST00000882153, ENST00000882154, ENST00000882155, ENST00000882156, ENST00000882157, ENST00000882158, ENST00000882159, ENST00000882160, ENST00000882161, ENST00000882162, ENST00000882163, ENST00000882164, ENST00000882165, ENST00000882166, ENST00000882167, ENST00000882168, ENST00000882169, ENST00000882170, ENST00000882171, ENST00000882172, ENST00000882173, ENST00000882174, ENST00000882175, ENST00000882176, ENST00000882177, ENST00000882178, ENST00000921444, ENST00000921445, ENST00000921446, ENST00000921447, ENST00000921448, ENST00000921449, ENST00000921450, ENST00000921451, ENST00000921452, ENST00000921453, ENST00000921454, ENST00000956229, ENST00000956230, ENST00000956231

RefSeq mRNA: 5 — MANE Select: NM_001077350 NM_001039476, NM_001077350, NM_001243247, NM_001243248, NM_001243249

CCDS: CCDS73794, CCDS73795

Canonical transcript exons

ENST00000611875 — 14 exons

Exon	Start	End
ENSE00001314268	88698	88890
ENSE00003459258	93219	93325
ENSE00003466209	112622	112775
ENSE00003472148	100372	100509
ENSE00003538360	119126	119255
ENSE00003589280	130522	130591
ENSE00003622190	117301	117375
ENSE00003624942	98145	98301
ENSE00003663199	138150	138334
ENSE00003672562	110525	110606
ENSE00003674129	92596	92725
ENSE00003683492	89713	89902
ENSE00003894302	138642	138673
ENSE00003896134	85386	86870

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 93.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.0812 / max 1031.6057, expressed in 1805 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155702	24.6354	1804
155701	1.1004	341
155703	0.3454	130

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood	UBERON:0000178	93.95	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.38	gold quality
right uterine tube	UBERON:0001302	92.32	gold quality
left ovary	UBERON:0002119	92.27	gold quality
right ovary	UBERON:0002118	92.13	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.85	gold quality
apex of heart	UBERON:0002098	91.26	gold quality
right adrenal gland	UBERON:0001233	90.98	gold quality
cerebellar hemisphere	UBERON:0002245	90.94	gold quality
cerebellar cortex	UBERON:0002129	90.80	gold quality
right adrenal gland cortex	UBERON:0035827	90.73	gold quality
gastrocnemius	UBERON:0001388	90.64	gold quality
right frontal lobe	UBERON:0002810	90.64	gold quality
left adrenal gland cortex	UBERON:0035825	90.40	gold quality
granulocyte	CL:0000094	90.39	gold quality
left adrenal gland	UBERON:0001234	90.37	gold quality
endocervix	UBERON:0000458	90.22	gold quality
muscle of leg	UBERON:0001383	90.22	gold quality
ganglionic eminence	UBERON:0004023	90.22	gold quality
stromal cell of endometrium	CL:0002255	90.09	gold quality
adenohypophysis	UBERON:0002196	89.95	gold quality
body of uterus	UBERON:0009853	89.92	gold quality
right lobe of thyroid gland	UBERON:0001119	89.73	gold quality
adrenal cortex	UBERON:0001235	89.58	gold quality
tibial nerve	UBERON:0001323	89.48	gold quality
left testis	UBERON:0004533	89.44	gold quality
ventricular zone	UBERON:0003053	89.40	gold quality
right testis	UBERON:0004534	89.28	gold quality
pituitary gland	UBERON:0000007	89.19	gold quality
cerebellum	UBERON:0002037	89.04	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-10	no	2.14
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI3, MAF, MAFB, MAX, MYB, NCOR2, TBP, TCF12, TFCP2

miRNA regulators (miRDB)

31 targeting NPRL3, 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-6508-5P	99.92	70.67	2465
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-4755-3P	98.77	65.59	1915
HSA-MIR-3691-5P	98.62	65.88	552
HSA-MIR-7114-5P	98.51	67.87	1349
HSA-MIR-548AT-3P	98.37	64.98	580
HSA-MIR-548AY-3P	98.37	65.14	562
HSA-MIR-637	97.91	64.05	1517
HSA-MIR-3665	97.73	65.08	975
HSA-MIR-3189-5P	97.55	66.71	655
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-5699-5P	97.36	67.03	1014
HSA-MIR-4726-5P	97.24	65.67	1299
HSA-MIR-939-5P	97.10	65.80	1579
HSA-MIR-500B-3P	96.49	65.40	1087
HSA-MIR-1343-5P	96.48	66.06	1506

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 17)

• C16orf35 can modulate differentially the specific activities of selected p73 isoforms. (PMID:19666006)
• NPRL3 is a target gene of the BACH1 transcription factor according to ChIP-seq analysis in HEK 293 cells. (PMID:21555518)
• NPRL3 is a candidate gene for harbouring mutations in individuals with developmental abnormalities of the cardiovascular system. (PMID:22538705)
• Mutations in NPRL3 are a novel cause of familial cortical dysplasia. (PMID:26285051)
• NPRL3 mutations are significant cause of focal epilepsy. (PMID:26505888)
• This study demonstrated that mutation of NPRL3 in familial focal epilepsies and focal cortical dysplasia. (PMID:27173016)
• overall, 63 distinct variants were identified: 53 in DEPDC5, three in NPRL2 and seven in NPRL3 . Among these, 46 were novel (including 39 single nucleotide variants and seven CNVs) and 16 were newly defined as recurrent variants; 34 were loss-of-function (LoF) variants (nonsense, splice-site, frameshift indels and CNVs). (PMID:30093711)
• Our results implicate the association of NPRL3 with hemimegalencephaly, expanding the phenotypic spectrum of NPRL3 in FFEVF and underlining that partial deletions are part of the genotypic spectrum of NPRL3 variants (PMID:31111464)
• A human minisatellite hosts an alternative transcription start site for NPRL3 driving its expression in a repeat number-dependent manner. (PMID:31898848)
• Diagnostic exome sequencing in non-acquired focal epilepsies highlights a major role of GATOR1 complex genes. (PMID:32086284)
• GATOR1-related focal cortical dysplasia in epilepsy surgery patients and their families: A possible gradient in severity? (PMID:33461085)
• Hemimegalencephaly and intractable seizures associated with the NPRL3 gene variant in a newborn: A case report. (PMID:33749980)
• Functional characterization of novel NPRL3 mutations identified in three families with focal epilepsy. (PMID:37071290)
• The clinical features of familial focal epilepsy with variable foci and NPRL3 gene variant. (PMID:37099548)
• Seizure features and outcomes in 50 children with GATOR1 variants: A retrospective study, more favorable for epilepsy surgery. (PMID:37259768)
• Refining the electroclinical spectrum of NPRL3-related epilepsy: A novel multiplex family and literature review. (PMID:37491868)
• Phenotypic and genotypic characterization of NPRL3-related epilepsy: Two case reports and literature review. (PMID:37902097)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nprl3	ENSDARG00000010918
mus_musculus	Nprl3	ENSMUSG00000020289
rattus_norvegicus	Nprl3	ENSRNOG00000020541
drosophila_melanogaster	Nprl3	FBGN0036397
caenorhabditis_elegans		WBGENE00018072

Protein

Protein identifiers

GATOR1 complex protein NPRL3 — Q12980 (reviewed: Q12980)

Alternative names: -14 gene protein, Alpha-globin regulatory element-containing gene protein, Nitrogen permease regulator 3-like protein, Protein CGTHBA

All UniProt accessions (10): Q12980, A0A087WTD0, A0A087WTE2, A0A087WTP7, B1B1F5, B7Z6Q0, F8WBJ1, F8WCB2, F8WDA5, F8WEK7

UniProt curated annotations — full annotation on UniProt →

Function. As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway. In response to amino acid depletion, the GATOR1 complex has GTPase activating protein (GAP) activity and strongly increases GTP hydrolysis by RagA/RRAGA (or RagB/RRAGB) within heterodimeric Rag complexes, thereby turning them into their inactive GDP-bound form, releasing mTORC1 from lysosomal surface and inhibiting mTORC1 signaling. In the presence of abundant amino acids, the GATOR1 complex is negatively regulated by GATOR2, the other GATOR subcomplex, in this amino acid-sensing branch of the TORC1 pathway.

Subunit / interactions. Within the GATOR complex, component of the GATOR1 subcomplex, made of DEPDC5, NPRL2 and NPRL3. GATOR1 mediates the strong interaction of the GATOR complex with small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD) heterodimers. GATOR1 interacts with GPR155/LYCHOS; interaction takes place in presence of cholesterol and prevents interaction between GATOR1 and KICSTOR.

Subcellular location. Lysosome membrane.

Tissue specificity. Widely expressed. Expressed in the frontal lobe cortex as well as in the temporal, parietal, and occipital lobes.

Disease relevance. Inactivating mutations and truncating deletions in the genes encoding GATOR1 proteins are detected in glioblastoma and ovarian tumors and are associated with loss of heterozygosity events. Inactivation of GATOR1 proteins promotes constitutive localization of mTORC1 to the lysosomal membrane and blocks mTORC1 inactivation following amino acid withdrawal. Epilepsy, familial focal, with variable foci 3 (FFEVF3) [MIM:617118] An autosomal dominant form of epilepsy characterized by focal seizures arising from different cortical regions, including the temporal, frontal, parietal, and occipital lobes. Seizure types commonly include temporal lobe epilepsy, frontal lobe epilepsy, and nocturnal frontal lobe epilepsy. Some patients may have intellectual disability or autism spectrum disorders. Seizure onset usually occurs in the first or second decades, although later onset has been reported, and there is phenotypic variability within families. A subset of patients have structural brain abnormalities. Penetrance of the disorder is incomplete. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the NPR3 family.

RefSeq proteins (5): NP_001034565, NP_001070818, NP_001230176, NP_001230177, NP_001230178 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005365	Npr3	Family
IPR056603	HTH_NPRL3	Domain

Pfam: PF03666, PF24064

UniProt features (45 total): helix 20, strand 13, turn 3, region of interest 2, compositionally biased region 2, sequence variant 2, chain 1, modified residue 1, sequence conflict 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
9V0J	ELECTRON MICROSCOPY	2.97
8FW5	ELECTRON MICROSCOPY	3.08
9O5A	ELECTRON MICROSCOPY	3.2
9O5D	ELECTRON MICROSCOPY	3.34
7T3B	ELECTRON MICROSCOPY	3.9
6CES	ELECTRON MICROSCOPY	4
7T3A	ELECTRON MICROSCOPY	4
7T3C	ELECTRON MICROSCOPY	4
6CET	ELECTRON MICROSCOPY	4.4
9O5E	ELECTRON MICROSCOPY	5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12980-F1	66.63	0.00

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 (1): 476

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9639288	Amino acids regulate mTORC1

MSigDB gene sets: 515 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, RNGTGGGC_UNKNOWN, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_REGULATION_OF_BLOOD_PRESSURE, E2F4DP1_01, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, GOCC_VACUOLAR_MEMBRANE, MODULE_64, GOBP_ARTERY_DEVELOPMENT

GO Biological Process (8): ventricular septum development (GO:0003281), positive regulation of autophagy (GO:0010508), cellular response to amino acid starvation (GO:0034198), aorta morphogenesis (GO:0035909), cardiac muscle tissue development (GO:0048738), roof of mouth development (GO:0060021), negative regulation of TORC1 signaling (GO:1904262), negative regulation of TOR signaling (GO:0032007)

GO Molecular Function (2): GTPase activator activity (GO:0005096), protein binding (GO:0005515)

GO Cellular Component (4): lysosomal membrane (GO:0005765), GATOR1 complex (GO:1990130), lysosome (GO:0005764), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cellular response to starvation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cardiac ventricle development	1
cardiac septum development	1
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
cellular response to starvation	1
response to amino acid starvation	1
aorta development	1
artery morphogenesis	1
heart development	1
striated muscle tissue development	1
anatomical structure development	1
negative regulation of TOR signaling	1
TORC1 signaling	1
regulation of TORC1 signaling	1
TOR signaling	1
regulation of TOR signaling	1
negative regulation of intracellular signal transduction	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
binding	1
lysosome	1
lytic vacuole membrane	1
protein-containing complex	1
Seh1-associated complex	1
lytic vacuole	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1282 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NPRL3	NPRL2	Q8WTW4	998
NPRL3	DEPDC5	O75140	998
NPRL3	WDR24	Q96S15	847
NPRL3	WDR59	Q6PJI9	846
NPRL3	MIOS	Q9NXC5	840
NPRL3	SEH1L	Q96EE3	810
NPRL3	RRAGC	Q9HB90	769
NPRL3	EFNA5	P52803	765
NPRL3	SEC13	P55735	764
NPRL3	RRAGA	Q7L523	758
NPRL3	RRAGB	Q5VZM2	747
NPRL3	KICS2	Q96MD2	722
NPRL3	SAMTOR	Q1RMZ1	715
NPRL3	RRAGD	Q9NQL2	713
NPRL3	KPTN	Q9Y664	706

IntAct

83 interactions, top by confidence:

A	B	Type	Score
NPRL3	NPRL2	psi-mi:“MI:0915”(physical association)	0.850
NPRL2	NPRL3	psi-mi:“MI:0914”(association)	0.850
NPRL2	NPRL3	psi-mi:“MI:0403”(colocalization)	0.850
NPRL2	NPRL3	psi-mi:“MI:0915”(physical association)	0.850
MIOS	SEC13	psi-mi:“MI:0914”(association)	0.790
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
ZNF414	AHCYL1	psi-mi:“MI:0914”(association)	0.640
WDR24	NPRL3	psi-mi:“MI:0914”(association)	0.600
SCGN	SNAP23	psi-mi:“MI:0914”(association)	0.550
SESN2	NPRL3	psi-mi:“MI:0914”(association)	0.530
SZT2	DEPDC5	psi-mi:“MI:0914”(association)	0.530
DEPDC5	NPRL3	psi-mi:“MI:0914”(association)	0.530
NPRL3	DEPDC5	psi-mi:“MI:0914”(association)	0.530
LRP1	NME4	psi-mi:“MI:0914”(association)	0.530
NPRL2	ZBTB5	psi-mi:“MI:0914”(association)	0.530
CAPN2	MYO9A	psi-mi:“MI:0914”(association)	0.530
SAMTOR	PER1	psi-mi:“MI:0914”(association)	0.530
ITFG2	DEPDC5	psi-mi:“MI:0914”(association)	0.530
SZT2	NPRL3	psi-mi:“MI:0914”(association)	0.500
SZT2	NPRL3	psi-mi:“MI:0915”(physical association)	0.500

BioGRID (146): NPRL3 (Two-hybrid), APPBP2 (Two-hybrid), NPRL3 (Affinity Capture-MS), NPRL3 (Affinity Capture-MS), NPRL3 (Affinity Capture-MS), NPRL3 (Affinity Capture-MS), NPRL3 (Affinity Capture-MS), NPRL3 (Affinity Capture-Western), NPRL3 (Affinity Capture-Western), NPRL3 (Affinity Capture-Western), NPRL3 (Affinity Capture-Western), NPRL3 (Affinity Capture-MS), NPRL3 (Affinity Capture-MS), NPRL3 (Affinity Capture-MS), NPRL3 (Affinity Capture-MS)

ESM2 similar proteins: A2AQW0, A2RV80, A6H7H7, B0LPN4, D4ABP9, E9Q401, E9Q4Z2, F1N9S8, F1QR43, O18756, O35099, O94923, P30957, Q0VEJ0, Q12980, Q14165, Q15386, Q5F361, Q5IH13, Q5IH14, Q5KSL6, Q5RCP7, Q5ZKG8, Q641K1, Q6NRD0, Q6NYU2, Q6WKZ8, Q6ZN16, Q80YV4, Q8BM85, Q8IWV8, Q8K2I9, Q8N6S4, Q8NFZ0, Q8TAP6, Q8TEA7, Q8VDD9, Q8VIJ8, Q8WWQ0, Q92736

Diamond homologs: Q12980, Q8VIJ8, Q9VUB4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NPRL3	“form complex”	GATOR1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 86 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
Amino acids regulate mTORC1	10	34.5×	7e-11
Cellular response to starvation	7	20.0×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of TORC1 signaling	11	45.7×	3e-13
cellular response to amino acid starvation	10	40.8×	1e-11
cellular response to glucose starvation	5	21.6×	7e-04
positive regulation of TORC1 signaling	5	18.9×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	42
Likely pathogenic	10
Uncertain significance	98
Likely benign	27
Benign	5

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072232	NC_000016.9:g.(?169115)(169264_?)del	Pathogenic
1072233	NC_000016.9:g.(?150360)(150517_?)del	Pathogenic
1076135	NC_000016.9:g.(?142584)(188266_?)del	Pathogenic
1076136	NC_000016.9:g.(?138677)(188286_?)del	Pathogenic
1076137	NC_000016.9:g.(?167290)(188266_?)del	Pathogenic
1076138	NC_000016.9:g.(?148133)(188266_?)del	Pathogenic
1076140	NC_000016.9:g.(?160513)(180600_?)del	Pathogenic
1076141	NC_000016.9:g.(?136684)(169274_?)del	Pathogenic
1407381	NC_000016.9:g.(?160503)(188266_?)del	Pathogenic
1418021	NC_000016.9:g.(?169105)(188266_?)del	Pathogenic
1452724	NC_000016.9:g.(?162601)(162794_?)del	Pathogenic
1455252	NC_000016.9:g.(?136705)(139740_?)del	Pathogenic
1457733	NC_000016.9:g.(?138677)(143343_?)del	Pathogenic
1457734	NC_000016.9:g.(?162601)(188266_?)del	Pathogenic
1460337	NC_000016.9:g.(?160503)(160624_?)del	Pathogenic
2042400	NM_001039476.1(NPRL3):c.931=	Pathogenic
2423599	NC_000016.9:g.(?188129)(193701_?)del	Pathogenic
2423601	NC_000016.9:g.(?143197)(150527_?)del	Pathogenic
2423602	NC_000016.9:g.(?142574)(150527_?)del	Pathogenic
2423610	NC_000016.9:g.(?143302)(152085_?)del	Pathogenic
2423612	NC_000016.9:g.(?188129)(188266_?)del	Pathogenic
2423613	NC_000016.9:g.(?160503)(180610_?)del	Pathogenic
2502348	NM_001077350.3:c.(118+1_119-1)_(188+1_189-1)del	Pathogenic
254357	NM_001077350.3(NPRL3):c.835dup (p.Ser279fs)	Pathogenic
3063424	GRCh37/hg19 16p13.3(chr16:143863-186659)x1	Pathogenic
3243545	NC_000016.9:g.(?136704)(188266_?)del	Pathogenic
3243547	NC_000016.9:g.(?148123)(148319_?)del	Pathogenic
3243548	NC_000016.9:g.(?169105)(193701_?)del	Pathogenic
3243551	NC_000016.9:g.(?180501)(188266_?)del	Pathogenic
3243552	NC_000016.9:g.(?167280)(180610_?)del	Pathogenic

SpliceAI

4582 predictions. Top by Δscore:

Variant	Effect	Δscore
16:100365:CACTT:C	donor_loss	1.0000
16:100366:ACTT:A	donor_loss	1.0000
16:100367:CTTA:C	donor_loss	1.0000
16:100368:TTAC:T	donor_loss	1.0000
16:100369:TA:T	donor_loss	1.0000
16:100370:A:AC	donor_gain	1.0000
16:100370:ACCGG:A	donor_loss	1.0000
16:100371:C:A	donor_loss	1.0000
16:100371:C:CC	donor_gain	1.0000
16:100506:CAGG:C	acceptor_gain	1.0000
16:100510:C:CC	acceptor_gain	1.0000
16:112618:TCA:T	donor_loss	1.0000
16:112620:A:AC	donor_gain	1.0000
16:112620:A:AT	donor_loss	1.0000
16:112620:AC:A	donor_gain	1.0000
16:112621:C:CT	donor_gain	1.0000
16:112621:CC:C	donor_gain	1.0000
16:112621:CCA:C	donor_gain	1.0000
16:112621:CCAT:C	donor_gain	1.0000
16:112774:GC:G	acceptor_gain	1.0000
16:112775:CC:C	acceptor_gain	1.0000
16:112777:T:A	acceptor_loss	1.0000
16:112780:A:T	acceptor_gain	1.0000
16:83254:AGGGT:A	donor_loss	1.0000
16:83255:GG:G	donor_gain	1.0000
16:83255:GGGTG:G	donor_loss	1.0000
16:83256:GG:G	donor_gain	1.0000
16:83256:GGTGA:G	donor_loss	1.0000
16:83257:G:GG	donor_gain	1.0000
16:83258:T:G	donor_loss	1.0000

AlphaMissense

3737 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:110543:A:G	L204P	1.000
16:119166:A:G	F93S	1.000
16:119187:A:G	L86P	1.000
16:110552:G:T	A201D	0.999
16:112670:C:G	A167P	0.999
16:112711:A:G	L153P	0.999
16:119160:C:T	G95E	0.999
16:119161:C:A	G95W	0.999
16:119161:C:G	G95R	0.999
16:119161:C:T	G95R	0.999
16:119163:A:T	V94D	0.999
16:119165:A:C	F93L	0.999
16:119165:A:T	F93L	0.999
16:119167:A:G	F93L	0.999
16:119229:A:T	I72N	0.999
16:119238:A:G	L69P	0.999
16:138197:A:G	F24S	0.999
16:138233:A:G	L12P	0.999
16:98173:G:T	A299D	0.999
16:110543:A:T	L204H	0.998
16:112681:A:G	L163P	0.998
16:112693:C:G	R159P	0.998
16:112735:A:G	L145P	0.998
16:117308:G:T	A129E	0.998
16:117311:A:G	F128S	0.998
16:117326:A:G	L123P	0.998
16:119154:G:T	P97Q	0.998
16:119166:A:C	F93C	0.998
16:119169:C:G	R92P	0.998
16:119181:A:T	I88N	0.998

dbSNP variants (sampled 300 via entrez): RS1000126812 (16:108774 G>T), RS1000144115 (16:122319 G>A,C), RS1000175581 (16:122617 C>G,T), RS1000295456 (16:99842 A>G,T), RS1000301743 (16:135600 C>A,T), RS1000355118 (16:135959 G>A,T), RS1000357646 (16:127530 C>T), RS1000372016 (16:92363 T>C), RS1000375825 (16:136465 G>A,T), RS1000421823 (16:110985 T>A,C), RS1000491332 (16:132250 C>T), RS1000499189 (16:108952 G>A,C), RS1000598301 (16:140555 T>C), RS1000610132 (16:87457 G>A), RS1000631919 (16:112136 T>C)

Disease associations

OMIM: gene MIM:600928 | disease phenotypes: MIM:617118, MIM:604131, MIM:604364

GenCC curated gene-disease

Disease	Classification	Inheritance
epilepsy, familial focal, with variable foci 3	Strong	Autosomal dominant
familial focal epilepsy with variable foci	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
focal epilepsy	Definitive	AD

Mondo (4): epilepsy, familial focal, with variable foci 3 (MONDO:0014925), alpha thalassemia spectrum (MONDO:0011399), epilepsy, familial focal, with variable foci 1 (MONDO:0024556), familial focal epilepsy with variable foci (MONDO:0020310)

Orphanet (1): Alpha-thalassemia (Orphanet:846)

HPO phenotypes

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

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000098	Tall stature
HP:0000272	Malar flattening
HP:0000545	Myopia
HP:0000708	Atypical behavior
HP:0000729	Autistic behavior
HP:0000767	Pectus excavatum
HP:0000980	Pallor
HP:0001166	Arachnodactyly
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001288	Gait disturbance
HP:0001382	Joint hypermobility
HP:0001634	Mitral valve prolapse
HP:0001763	Pes planus
HP:0001847	Long hallux
HP:0002069	Bilateral tonic-clonic seizure
HP:0002126	Polymicrogyria
HP:0002349	Focal aware seizure
HP:0002367	Visual hallucination
HP:0002384	Focal impaired awareness seizure
HP:0002427	Expressive aphasia
HP:0002521	Hypsarrhythmia
HP:0002616	Aortic root aneurysm
HP:0003401	Paresthesia
HP:0003829	Typified by incomplete penetrance
HP:0007206	Hemimegalencephaly
HP:0007359	Focal-onset seizure
HP:0008765	Auditory hallucination

GWAS associations

58 associations (top):

Study	Trait	p-value
GCST001765_19	Red blood cell traits	6.000000e-23
GCST001862_3	Sickle cell anemia (haemolysis)	2.000000e-09
GCST001873_3	Red blood cell traits	3.000000e-23
GCST001873_5	Red blood cell traits	9.000000e-48
GCST001873_6	Red blood cell traits	2.000000e-34
GCST001873_8	Red blood cell traits	4.000000e-22
GCST003122_1	Hemoglobin levels	6.000000e-18
GCST004334_3	Mean corpuscular hemoglobin	8.000000e-12
GCST004335_6	Mean corpuscular volume	6.000000e-08
GCST004601_132	Red blood cell count	6.000000e-27
GCST004601_133	Red blood cell count	1.000000e-34
GCST004602_216	Mean corpuscular volume	4.000000e-82
GCST004602_217	Mean corpuscular volume	6.000000e-101
GCST004605_7	Mean corpuscular hemoglobin concentration	7.000000e-37
GCST004605_8	Mean corpuscular hemoglobin concentration	1.000000e-28
GCST004612_142	High light scatter reticulocyte percentage of red cells	3.000000e-11
GCST004619_153	Reticulocyte fraction of red cells	6.000000e-23
GCST004630_163	Mean corpuscular hemoglobin	9.000000e-11
GCST004630_164	Mean corpuscular hemoglobin	2.000000e-100
GCST004630_165	Mean corpuscular hemoglobin	5.000000e-130
GCST005992_20	Mean corpuscular hemoglobin concentration	7.000000e-30
GCST005993_12	Mean corpuscular hemoglobin	2.000000e-78
GCST005996_2	Red blood cell count	2.000000e-12
GCST006011_44	Mean corpuscular volume	5.000000e-55
GCST006101_17	Cardiometabolic and hematological traits	4.000000e-13
GCST010083_276	Hemoglobin levels	2.000000e-10
GCST012020_145	Serum metabolite levels	2.000000e-12
GCST90002384_351	Hemoglobin	6.000000e-17
GCST90002385_62	High light scatter reticulocyte count	4.000000e-14
GCST90002385_63	High light scatter reticulocyte count	2.000000e-10

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin
EFO:0004509	hemoglobin measurement
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0007629	hemoglobin A1 measurement
EFO:0004305	erythrocyte count
EFO:0007986	reticulocyte count
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D017085	alpha-Thalassemia	C15.378.050.141.150.875.100; C15.378.420.826.100; C16.320.070.875.100; C16.320.365.826.100
C565785	Epilepsy, Partial, with Variable Foci (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	decreases expression	3
mercuric bromide	decreases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Valproic Acid	decreases expression, affects expression	2
dicrotophos	increases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
beta-lapachone	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
methacrylaldehyde	decreases expression, increases abundance, affects cotreatment	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	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Vorinostat	decreases expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Air Pollutants	increases abundance, affects cotreatment, decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases expression	1
Carbamazepine	affects expression	1
Dieldrin	increases response to substance	1
Doxorubicin	affects expression	1
Nickel	decreases expression	1
Ozone	decreases expression, increases abundance, affects cotreatment	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Thimerosal	decreases expression	1

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D6LF	SDCHi002-A	Induced pluripotent stem cell	Male
CVCL_TA96	HAP1 NPRL3 (-) 1	Cancer cell line	Male
CVCL_TA97	HAP1 NPRL3 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02986698	PHASE1	TERMINATED	In Utero Hematopoietic Stem Cell Transplantation for Alpha-thalassemia Major (ATM)
NCT01419704	PHASE1/PHASE2	WITHDRAWN	Phase I/II Pilot Study of Mixed Chimerism to Treat Hemoglobinopathies
NCT00159029	Not specified	COMPLETED	Genetics of Alpha Thalassemia in Israeli Ethnic Groups
NCT02692872	Not specified	ACTIVE_NOT_RECRUITING	Screening for Alpha Thalassemia in Healthy Volunteers
NCT04872179	Not specified	RECRUITING	International Registry of Patients With Alpha Thalassemia
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06539169	Not specified	RECRUITING	FLOWER: Following Longitudinal Outcomes With Epidemiology for Rare Diseases
NCT06591936	Not specified	RECRUITING	Genetic Profile of Alpha Thalassemia Children at Sohag University Hospital .
NCT06831799	Not specified	COMPLETED	ERN-EuroBloodNet Registry on Patients With Rare Red Blood Cell Defects and COVID-19