TECPR2

Summary

TECPR2 (tectonin beta-propeller repeat containing 2, HGNC:19957) is a protein-coding gene on chromosome 14q32.33, encoding Tectonin beta-propeller repeat-containing protein 2 (O15040). Probably plays a role as positive regulator of autophagy.

The protein encoded by this gene is a member of the tectonin beta-propeller repeat-containing (TECPR) family, and contains both TECPR and tryptophan-aspartic acid repeat (WD repeat) domains. This gene has been implicated in autophagy, as reduced expression levels of this gene have been associated with impaired autophagy. Recessive mutations in this gene have been associated with a hereditary form of spastic paraparesis (HSP). HSP is characterized by progressive spasticity and paralysis of the legs. There is also some evidence linking mutations in this gene with birdshot chorioretinopathy (BSCR), which results in inflammation of the choroid and retina. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 9895 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary spastic paraplegia 49 (Strong, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 1,563 total — 62 pathogenic, 56 likely-pathogenic
• Phenotypes (HPO): 30
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_014844

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19957
Approved symbol	TECPR2
Name	tectonin beta-propeller repeat containing 2
Location	14q32.33
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000196663
Ensembl biotype	protein_coding
OMIM	615000
Entrez	9895

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 4 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000359520, ENST00000557786, ENST00000558678, ENST00000559124, ENST00000560060, ENST00000561099, ENST00000561228, ENST00000856897, ENST00000971423

RefSeq mRNA: 2 — MANE Select: NM_014844 NM_001172631, NM_014844

CCDS: CCDS32162, CCDS58337

Canonical transcript exons

ENST00000359520 — 20 exons

Exon	Start	End
ENSE00000660496	102465141	102465289
ENSE00000941518	102424979	102425291
ENSE00000941519	102428250	102428382
ENSE00000941521	102434235	102435211
ENSE00000941525	102445806	102445947
ENSE00000941526	102449629	102449869
ENSE00001327614	102496979	102497120
ENSE00001375381	102431796	102432128
ENSE00001434925	102498103	102502477
ENSE00001506925	102452394	102452627
ENSE00001506926	102450560	102450649
ENSE00001548807	102362941	102363116
ENSE00003464374	102497570	102497719
ENSE00003472341	102438022	102438205
ENSE00003488889	102443647	102443827
ENSE00003510872	102414636	102414793
ENSE00003575800	102440436	102440609
ENSE00003608986	102376650	102376940
ENSE00003625739	102407338	102407466
ENSE00003663805	102408488	102408619

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 94.14.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.4322 / max 262.0514, expressed in 1775 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
141653	4.7493	1584
141655	4.1985	1635
141654	1.4845	608

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	94.14	gold quality
lateral globus pallidus	UBERON:0002476	91.39	gold quality
inferior vagus X ganglion	UBERON:0005363	91.37	gold quality
substantia nigra pars reticulata	UBERON:0001966	91.08	gold quality
oocyte	CL:0000023	90.92	gold quality
substantia nigra pars compacta	UBERON:0001965	90.81	gold quality
corpus callosum	UBERON:0002336	90.41	gold quality
lateral nuclear group of thalamus	UBERON:0002736	90.16	gold quality
blood	UBERON:0000178	90.13	gold quality
entorhinal cortex	UBERON:0002728	90.11	gold quality
middle temporal gyrus	UBERON:0002771	90.03	gold quality
Brodmann (1909) area 23	UBERON:0013554	89.44	gold quality
subthalamic nucleus	UBERON:0001906	88.76	gold quality
prefrontal cortex	UBERON:0000451	88.72	gold quality
CA1 field of hippocampus	UBERON:0003881	88.66	gold quality
ventral tegmental area	UBERON:0002691	88.45	gold quality
globus pallidus	UBERON:0001875	88.38	gold quality
pigmented layer of retina	UBERON:0001782	88.23	gold quality
parietal lobe	UBERON:0001872	88.07	gold quality
medulla oblongata	UBERON:0001896	87.89	gold quality
postcentral gyrus	UBERON:0002581	87.89	gold quality
dorsal plus ventral thalamus	UBERON:0001897	87.63	gold quality
medial globus pallidus	UBERON:0002477	87.36	gold quality
inferior olivary complex	UBERON:0002127	87.14	gold quality
superior frontal gyrus	UBERON:0002661	87.14	gold quality
frontal cortex	UBERON:0001870	86.88	gold quality
superior vestibular nucleus	UBERON:0007227	86.85	gold quality
temporal lobe	UBERON:0001871	86.61	gold quality
sperm	CL:0000019	86.47	silver quality
Brodmann (1909) area 46	UBERON:0006483	86.33	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.79

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

170 targeting TECPR2, 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-5692A	100.00	74.40	6850
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6793-5P	99.97	65.95	758
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-3910	99.95	71.13	2227

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 9)

• The discovered TECPR2 mutation implicates autophagy, a central intracellular mechanism, in spastic paraparesis. (PMID:23176824)
• Results show that TECPR2 associates with several trafficking components as SEC24D and cooperates with LC3C to regulate ER exit sites and ER export suggesting that TECPR2 functions as molecular scaffold linking early secretion pathway and autophagy. (PMID:26431026)
• The discovery of additional TECPR2 utations in non-Bukharian patients implies that this disease might be more common than previously appreciated (PMID:26542466)
• Whole exome sequencing in an Italian pedigree suggests involvement of TECPR2 in a complex form of progressive motor neuron disease. (PMID:27406698)
• The first was the Tectonin beta-propeller repeat containing 2 gene (TECPR2), with allele G on rs10149146 present in 15 controls and no AD cases. The Fisher exact test revealed statistically significant association to healthy brain aging with SNP rs10149146 on TECPR2 (P-value=4.055e-4). (PMID:30681437)
• Lysosomal targeting of autophagosomes by the TECPR domain of TECPR2. (PMID:33213269)
• Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability. (PMID:33847017)
• Multimodal bioinformatic analyses of the neurodegenerative disease-associated TECPR2 gene reveal its diverse roles. (PMID:34933910)
• TECPR2-related hereditary sensory and autonomic neuropathy in two siblings from Palestine. (PMID:38436550)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tecpr2	ENSDARG00000060835
mus_musculus	Tecpr2	ENSMUSG00000021275
rattus_norvegicus	Tecpr2	ENSRNOG00000021904
drosophila_melanogaster	CG11141	FBGN0033177
caenorhabditis_elegans	W09G3.6	WBGENE00012369

Paralogs (1): HPS5 (ENSG00000110756)

Protein

Protein identifiers

Tectonin beta-propeller repeat-containing protein 2 — O15040 (reviewed: O15040)

Alternative names: WD repeat-containing protein KIAA0329/KIAA0297

All UniProt accessions (1): O15040

UniProt curated annotations — full annotation on UniProt →

Function. Probably plays a role as positive regulator of autophagy.

Subunit / interactions. Interacts with the ATG8 family members GABARAP, GABARAPL1, GABARAPL2, MAP1LC3B and MAP1LC3C.

Tissue specificity. Detected in skin fibroblast (at protein level).

Disease relevance. Neuropathy, hereditary sensory and autonomic, 9, with developmental delay (HSAN9) [MIM:615031] A form of hereditary sensory and autonomic neuropathy, a genetically and clinically heterogeneous group of disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and by sensory and/or autonomic abnormalities. HSAN9 is characterized by global developmental delay and intellectual disability, axial and appendicular hypotonia, dysarthria, and an abnormal gait that is often described as ataxic. Other features may include peripheral neuropathy, hyporeflexia, and autonomic dysfunction. Affected individuals also have dysmorphic features, thin corpus callosum on brain imaging, and episodes of central apnea, which may be fatal. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the WD repeat KIAA0329 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O15040-1	1	yes
O15040-2	2

RefSeq proteins (2): NP_001166102, NP_055659* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR006624	Beta-propeller_rpt_TECPR	Repeat
IPR009091	RCC1/BLIP-II	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR056499	Beta-prop_HPS5-like	Domain

Pfam: PF06462, PF19193, PF23756

UniProt features (31 total): repeat 13, region of interest 5, compositionally biased region 5, sequence variant 4, splice variant 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15040-F1	68.27	0.38

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 189 (showing top): GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, ATACCTC_MIR202, MODULE_503, GTGCCTT_MIR506, MODULE_195, MODULE_147, chr14q32, GOBP_PROTEIN_EXIT_FROM_ENDOPLASMIC_RETICULUM, MODULE_356, PARENT_MTOR_SIGNALING_UP, POS_RESPONSE_TO_HISTAMINE_UP, DODD_NASOPHARYNGEAL_CARCINOMA_DN, JOHNSTONE_PARVB_TARGETS_3_DN, TORCHIA_TARGETS_OF_EWSR1_FLI1_FUSION_UP, PURBEY_TARGETS_OF_CTBP1_NOT_SATB1_DN

GO Biological Process (2): autophagy (GO:0006914), protein exit from endoplasmic reticulum (GO:0032527)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (1): cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
cytoplasm	1
intracellular protein transport	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

968 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TECPR2	GABARAPL2	P60520	838
TECPR2	F5GZY7	F5GZY7	833
TECPR2	MAP1LC3C	Q9BXW4	796
TECPR2	SPG11	Q96JI7	733
TECPR2	AP5Z1	O43299	720
TECPR2	DDHD1	Q8NEL9	687
TECPR2	PLA2G6	O60733	670
TECPR2	SPG21	Q9NZD8	668
TECPR2	ZFYVE26	Q68DK2	663
TECPR2	MAP1LC3B	Q9GZQ8	643
TECPR2	B4GALNT1	Q00973	640
TECPR2	ATG12	O94817	626
TECPR2	WDR45	Q9Y484	625
TECPR2	AP4S1	Q9Y587	622
TECPR2	EPG5	Q9HCE0	607

IntAct

138 interactions, top by confidence:

A	B	Type	Score
GABARAP	IPO5	psi-mi:“MI:0914”(association)	0.590
TECPR2	GABARAPL1	psi-mi:“MI:0407”(direct interaction)	0.540
TECPR2	GABARAPL2	psi-mi:“MI:0407”(direct interaction)	0.540
MAP1LC3C	TECPR2	psi-mi:“MI:0407”(direct interaction)	0.540
GABARAPL1	TECPR2	psi-mi:“MI:0915”(physical association)	0.540
TECPR2	GABARAPL2	psi-mi:“MI:0915”(physical association)	0.540
TECPR2	MAP1LC3C	psi-mi:“MI:0915”(physical association)	0.540
TECPR2	GABARAP	psi-mi:“MI:0407”(direct interaction)	0.520
MAP1LC3B	TECPR2	psi-mi:“MI:0407”(direct interaction)	0.440
TECPR2	PARD3	psi-mi:“MI:0407”(direct interaction)	0.440
TECPR2	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.440
TECPR2	GORASP2	psi-mi:“MI:0407”(direct interaction)	0.440
TECPR2	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
TECPR2	PARD3B	psi-mi:“MI:0407”(direct interaction)	0.440
LNX2	TECPR2	psi-mi:“MI:0407”(direct interaction)	0.440
TECPR2	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
TECPR2	GORASP1	psi-mi:“MI:0407”(direct interaction)	0.440
TECPR2	HTRA3	psi-mi:“MI:0407”(direct interaction)	0.440
TECPR2	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
TECPR2	TIAM2	psi-mi:“MI:0407”(direct interaction)	0.440
TECPR2	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	TECPR2	psi-mi:“MI:0407”(direct interaction)	0.440
TECPR2	PDZRN4	psi-mi:“MI:0407”(direct interaction)	0.440
TECPR2	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
TECPR2	MPP2	psi-mi:“MI:0407”(direct interaction)	0.440
TECPR2	GOPC	psi-mi:“MI:0407”(direct interaction)	0.440
TECPR2	GRID2IP	psi-mi:“MI:0407”(direct interaction)	0.440
TECPR2	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
TECPR2	APBA2	psi-mi:“MI:0407”(direct interaction)	0.440
TECPR2	TJP1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (22): VPS41 (Affinity Capture-MS), VPS18 (Affinity Capture-MS), VPS16 (Affinity Capture-MS), PPM1A (Affinity Capture-MS), NUDCD3 (Affinity Capture-MS), DNAJB5 (Affinity Capture-MS), TECPR2 (Affinity Capture-RNA), TECPR2 (Affinity Capture-RNA), TECPR2 (Two-hybrid), TECPR2 (Affinity Capture-RNA), TECPR2 (Proximity Label-MS), VPS16 (Affinity Capture-MS), NUDCD3 (Affinity Capture-MS), VPS41 (Affinity Capture-MS), PPM1A (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8GLK3, A0A974CYQ5, A2AHJ4, A5WW08, D2HNY3, D2HWM5, E7F6T8, F1ND48, O15040, O70260, O95071, P59328, Q3TLR7, Q4V837, Q58DC2, Q58WW2, Q5E9J6, Q5F479, Q5FWP4, Q5NVC7, Q5R9B8, Q5RF77, Q5RGA4, Q5RHI5, Q5ZLG9, Q62671, Q66JG1, Q6DDH2, Q6P1W0, Q6P256, Q6PCD5, Q6PJI9, Q6RI45, Q80TP3, Q80U93, Q810L3, Q8C0M0, Q8CBW4, Q8CIK8, Q8CIN9

Diamond homologs: O15040, P59438, Q6NLL1, Q297N8, Q9UPZ3, Q9VHN9

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 89 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
Ras activation upon Ca2+ influx through NMDA receptor	5	47.6×	3e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	45.3×	3e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	45.3×	3e-06
Long-term potentiation	5	39.6×	5e-06
Assembly and cell surface presentation of NMDA receptors	9	38.1×	2e-10
Neurexins and neuroligins	10	32.8×	8e-11
Protein-protein interactions at synapses	6	26.6×	4e-06
RHOB GTPase cycle	5	12.9×	9e-04

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	74.3×	6e-16
protein localization to synapse	6	53.4×	2e-07
receptor clustering	7	50.8×	2e-08
regulation of postsynaptic membrane neurotransmitter receptor levels	7	40.3×	7e-08
autophagosome maturation	5	20.4×	2e-04
mitophagy	5	18.5×	3e-04
autophagosome assembly	5	13.1×	1e-03
protein-containing complex assembly	9	11.9×	4e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

1563 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	62
Likely pathogenic	56
Uncertain significance	385
Likely benign	916
Benign	67

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071213	NM_014844.5(TECPR2):c.34G>T (p.Glu12Ter)	Pathogenic
1071450	NM_014844.5(TECPR2):c.1160_1161del (p.Thr387fs)	Pathogenic
1072053	NM_014844.5(TECPR2):c.3326G>A (p.Trp1109Ter)	Pathogenic
1072374	NM_014844.5(TECPR2):c.3946C>T (p.Gln1316Ter)	Pathogenic
1072499	NM_014844.5(TECPR2):c.877del (p.Ser293fs)	Pathogenic
1073499	NM_014844.5(TECPR2):c.2915G>A (p.Trp972Ter)	Pathogenic
1073977	NM_014844.5(TECPR2):c.3469_3470del (p.Gln1157fs)	Pathogenic
1074322	NM_014844.5(TECPR2):c.2599G>T (p.Glu867Ter)	Pathogenic
1076042	NC_000014.8:g.(?102891306)(102901558_?)del	Pathogenic
1350644	NM_014844.5(TECPR2):c.1152del (p.Ala386fs)	Pathogenic
1356743	NM_014844.5(TECPR2):c.3686G>A (p.Trp1229Ter)	Pathogenic
1360096	NM_014844.5(TECPR2):c.3396del (p.Thr1133fs)	Pathogenic
1375508	NM_014844.5(TECPR2):c.2988_2989del (p.Trp997fs)	Pathogenic
1414294	NM_014844.5(TECPR2):c.3737_3738del (p.Leu1246fs)	Pathogenic
1414575	NM_014844.5(TECPR2):c.1834_1835del (p.Gln612fs)	Pathogenic
1451298	NC_000014.8:g.(?102894577)(102894729_?)del	Pathogenic
1458279	NM_014844.5(TECPR2):c.728G>A (p.Trp243Ter)	Pathogenic
1460289	NM_014844.5(TECPR2):c.3942del (p.Cys1315fs)	Pathogenic
1924891	NM_014844.5(TECPR2):c.3918G>A (p.Trp1306Ter)	Pathogenic
1943704	NM_014844.5(TECPR2):c.1470_1471insT (p.Glu491Ter)	Pathogenic
2014529	NM_014844.5(TECPR2):c.3106C>T (p.Gln1036Ter)	Pathogenic
2045726	NM_014844.5(TECPR2):c.2224C>T (p.Gln742Ter)	Pathogenic
2061762	NM_014844.5(TECPR2):c.1083del (p.Thr361_Val362insTer)	Pathogenic
2092022	NM_014844.5(TECPR2):c.1328_1329del (p.Arg443fs)	Pathogenic
2093490	NM_014844.5(TECPR2):c.2955del (p.Val986fs)	Pathogenic
2094947	NM_014844.5(TECPR2):c.1360C>T (p.Gln454Ter)	Pathogenic
2096627	NM_014844.5(TECPR2):c.3619_3628dup (p.Leu1210fs)	Pathogenic
2107566	NM_014844.5(TECPR2):c.3750_3763dup (p.Trp1255fs)	Pathogenic
2112808	NM_014844.5(TECPR2):c.1529_1557dup (p.Ser520delinsValSerTrpAlaValAlaTrpIleSerTer)	Pathogenic
2134888	NM_014844.5(TECPR2):c.2649del (p.Lys884fs)	Pathogenic

SpliceAI

4359 predictions. Top by Δscore:

Variant	Effect	Δscore
14:102376939:AGG:A	donor_loss	1.0000
14:102376941:GTGA:G	donor_loss	1.0000
14:102376942:T:A	donor_loss	1.0000
14:102407325:A:AG	acceptor_gain	1.0000
14:102407325:AAC:A	acceptor_gain	1.0000
14:102407327:C:CA	acceptor_gain	1.0000
14:102407327:C:G	acceptor_gain	1.0000
14:102407334:CCAGG:C	acceptor_loss	1.0000
14:102407335:CAGGG:C	acceptor_loss	1.0000
14:102407336:A:AG	acceptor_gain	1.0000
14:102407336:AG:A	acceptor_gain	1.0000
14:102407336:AGG:A	acceptor_gain	1.0000
14:102407337:G:A	acceptor_loss	1.0000
14:102407337:G:GG	acceptor_gain	1.0000
14:102407337:GG:G	acceptor_gain	1.0000
14:102407337:GGG:G	acceptor_gain	1.0000
14:102407337:GGGGA:G	acceptor_gain	1.0000
14:102407466:GGTG:G	donor_loss	1.0000
14:102407467:G:GG	donor_gain	1.0000
14:102407467:GTG:G	donor_loss	1.0000
14:102428378:AACAG:A	donor_loss	1.0000
14:102428381:AGGT:A	donor_loss	1.0000
14:102428383:G:GA	donor_loss	1.0000
14:102428384:T:A	donor_loss	1.0000
14:102431794:A:AG	acceptor_gain	1.0000
14:102431795:G:GG	acceptor_gain	1.0000
14:102431795:GT:G	acceptor_gain	1.0000
14:102431795:GTGA:G	acceptor_gain	1.0000
14:102432106:G:GT	donor_gain	1.0000
14:102435210:AGGTA:A	donor_loss	1.0000

AlphaMissense

9254 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:102443808:T:A	W972R	1.000
14:102443808:T:C	W972R	1.000
14:102465263:T:A	W1255R	1.000
14:102465263:T:C	W1255R	1.000
14:102408542:T:A	W135R	0.999
14:102408542:T:C	W135R	0.999
14:102425067:T:A	W243R	0.999
14:102425067:T:C	W243R	0.999
14:102438157:T:A	W844R	0.999
14:102438157:T:C	W844R	0.999
14:102440447:T:A	W864R	0.999
14:102440447:T:C	W864R	0.999
14:102440481:C:A	A875D	0.999
14:102440516:T:A	W887R	0.999
14:102440516:T:C	W887R	0.999
14:102440568:C:A	A904D	0.999
14:102440570:T:A	W905R	0.999
14:102440570:T:C	W905R	0.999
14:102443665:C:A	P924H	0.999
14:102452600:T:A	W1205R	0.999
14:102452600:T:C	W1205R	0.999
14:102497096:G:T	G1303W	0.999
14:102497105:T:A	W1306R	0.999
14:102497105:T:C	W1306R	0.999
14:102497683:T:A	W1349R	0.999
14:102497683:T:C	W1349R	0.999
14:102376875:A:C	S52R	0.998
14:102376877:C:A	S52R	0.998
14:102376877:C:G	S52R	0.998
14:102407396:C:A	A93E	0.998

dbSNP variants (sampled 300 via entrez): RS1000006834 (14:102422625 G>A), RS1000007280 (14:102461942 C>G), RS1000012304 (14:102381712 A>G), RS1000031428 (14:102419243 C>T), RS1000069711 (14:102382070 G>A,T), RS1000127713 (14:102441896 T>G), RS1000162651 (14:102429147 G>A), RS1000177540 (14:102458695 C>T), RS1000183683 (14:102442176 A>G), RS1000190986 (14:102404422 T>C,G), RS1000217985 (14:102394635 C>T), RS1000235683 (14:102429536 C>T), RS1000239095 (14:102474802 C>A,T), RS1000243055 (14:102468331 G>A), RS1000282030 (14:102393881 C>T)

Disease associations

OMIM: gene MIM:615000 | disease phenotypes: MIM:615031, MIM:303350, MIM:209850, MIM:136630

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary spastic paraplegia 49	Strong	Autosomal recessive

Mondo (6): hereditary spastic paraplegia 49 (MONDO:0014016), hereditary spastic paraplegia (MONDO:0019064), intellectual disability (MONDO:0001071), autism (MONDO:0005260), intellectual disability, FRA12A type (MONDO:0007634), microcephaly (MONDO:0001149)

Orphanet (3): Hereditary sensory and autonomic neuropathy due to TECPR2 mutation (Orphanet:320385), Hereditary spastic paraplegia (Orphanet:685), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

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

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000293	Full cheeks
HP:0000294	Low anterior hairline
HP:0000311	Round face
HP:0000338	Hypomimic face
HP:0000470	Short neck
HP:0000475	Broad neck
HP:0000678	Dental crowding
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001258	Spastic paraplegia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001284	Areflexia
HP:0001290	Generalized hypotonia
HP:0001310	Dysmetria
HP:0002020	Gastroesophageal reflux
HP:0002059	Cerebral atrophy
HP:0002064	Spastic gait
HP:0002066	Gait ataxia
HP:0002069	Bilateral tonic-clonic seizure
HP:0002079	Hypoplasia of the corpus callosum
HP:0002205	Recurrent respiratory infections
HP:0002871	Central apnea
HP:0004322	Short stature
HP:0011463	Childhood onset

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002501_2	Birdshot chorioretinopathy	2.000000e-07
GCST004603_143	Platelet count	5.000000e-18
GCST005951_8	Body mass index	7.000000e-09
GCST010002_161	Refractive error	1.000000e-20
GCST90000025_202	Appendicular lean mass	8.000000e-14

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0004340	body mass index
EFO:0004980	appendicular lean mass

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C566980	Mental Retardation, Fra12a Type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, affects methylation	2
GSK-J4	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, decreases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	increases expression	1
sulphoraphene	decreases expression	1
(+)-JQ1 compound	increases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Norethindrone Acetate	affects cotreatment, increases expression	1
Arsenic	affects methylation	1
Atrazine	increases expression	1
Azacitidine	increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Estradiol	increases expression, affects cotreatment	1
Phthalic Acids	increases methylation	1
Valproic Acid	affects expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Cyclosporine	increases methylation	1
Aflatoxin B1	affects methylation	1
Copper Sulfate	decreases expression	1
Vitamin K 3	affects expression	1
Magnetite Nanoparticles	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TR88	HAP1 TECPR2 (-) 1	Cancer cell line	Male
CVCL_TR89	HAP1 TECPR2 (-) 2	Cancer cell line	Male
CVCL_TR90	HAP1 TECPR2 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT06478238	EARLY_PHASE1	RECRUITING	Calcium Folinate Treatment of Spastic Paraplegia 56
NCT00023075	Not specified	COMPLETED	Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00677768	Not specified	COMPLETED	Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)
NCT01568658	Not specified	ACTIVE_NOT_RECRUITING	Genetic and Physical Study of Childhood Nerve and Muscle Disorders
NCT02327845	Not specified	ENROLLING_BY_INVITATION	Phenotype, Genotype & Biomarkers in ALS and Related Disorders
NCT02852278	Not specified	COMPLETED	A Patient Centric Motor Neuron Disease Activities of Daily Living Scale
NCT02859428	Not specified	TERMINATED	Disease Natural History and Biomarkers of SPG3A, SPG4A, and SPG31
NCT03104088	Not specified	COMPLETED	Studying Cognition in SPG4
NCT03206190	Not specified	RECRUITING	The preSPG4 Study - Studying the Prodromal and Early Phase of SPG4
NCT03627416	Not specified	COMPLETED	Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy
NCT03981276	Not specified	RECRUITING	Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders
NCT04006418	Not specified	RECRUITING	A Registered Cohort Study on Spastic Paraplegia
NCT04180098	Not specified	COMPLETED	Improving Gait Adaptability in Hereditary Spastic Paraplegia
NCT04256681	Not specified	COMPLETED	SNAP: Measurement of the Subjective Perception of the Symptom in Hereditary Spastic Paraparesis (HSP)
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia
NCT04875416	Not specified	ACTIVE_NOT_RECRUITING	Phenotype, Genotype and Biomarkers 2