C19orf12

Summary

C19orf12 (chromosome 19 open reading frame 12, HGNC:25443) is a protein-coding gene on chromosome 19q12, encoding Protein C19orf12 (Q9NSK7).

This gene encodes a small transmembrane protein. Mutations in this gene are a cause of neurodegeneration with brain iron accumulation-4 (NBIA4), but the specific function of the encoded protein is unknown. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 83636 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodegeneration with brain iron accumulation 4 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 345 total — 14 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 48
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_031448

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25443
Approved symbol	C19orf12
Name	chromosome 19 open reading frame 12
Location	19q12
Locus type	gene with protein product
Status	Approved
Aliases	MGC10922, DKFZP762D096, NBIA4, MPAN
Ensembl gene	ENSG00000131943
Ensembl biotype	protein_coding
OMIM	614297
Entrez	83636

Gene structure

Transcript identifiers

Ensembl transcripts: 41 — 40 protein_coding, 1 nonsense_mediated_decay

ENST00000323670, ENST00000342680, ENST00000392275, ENST00000392276, ENST00000591243, ENST00000592153, ENST00000614091, ENST00000623113, ENST00000890432, ENST00000890433, ENST00000890434, ENST00000890435, ENST00000890436, ENST00000890437, ENST00000890438, ENST00000890439, ENST00000890440, ENST00000890441, ENST00000890442, ENST00000890443, ENST00000890444, ENST00000890445, ENST00000890446, ENST00000890447, ENST00000890448, ENST00000890449, ENST00000890450, ENST00000890451, ENST00000890452, ENST00000946392, ENST00000946393, ENST00000946394, ENST00000946395, ENST00000946396, ENST00000946397, ENST00000946398, ENST00000946399, ENST00000946400, ENST00000946401, ENST00000946402, ENST00000946403

RefSeq mRNA: 7 — MANE Select: NM_031448 NM_001031726, NM_001256046, NM_001256047, NM_001282929, NM_001282930, NM_001282931, NM_031448

CCDS: CCDS12418, CCDS59373, CCDS74325

Canonical transcript exons

ENST00000323670 — 3 exons

Exon	Start	End
ENSE00001265331	29698937	29702977
ENSE00001511291	29715125	29715261
ENSE00003503212	29708254	29708423

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 98.49.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.4618 / max 180.7588, expressed in 1742 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
180371	6.3309	1729
180370	1.3597	809
180364	0.7510	103
180363	0.3316	73
180369	0.2435	94
180366	0.1597	56
180365	0.1319	49
180362	0.0664	33
180368	0.0610	28
180367	0.0261	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	98.49	gold quality
kidney epithelium	UBERON:0004819	97.35	gold quality
epithelial cell of pancreas	CL:0000083	96.59	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.05	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.67	gold quality
left ventricle myocardium	UBERON:0006566	95.49	gold quality
middle temporal gyrus	UBERON:0002771	95.36	gold quality
biceps brachii	UBERON:0001507	94.87	gold quality
deltoid	UBERON:0001476	94.76	gold quality
pancreatic ductal cell	CL:0002079	94.55	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.52	gold quality
tibialis anterior	UBERON:0001385	94.41	silver quality
gastrocnemius	UBERON:0001388	94.33	gold quality
vastus lateralis	UBERON:0001379	94.31	gold quality
muscle of leg	UBERON:0001383	94.28	gold quality
heart right ventricle	UBERON:0002080	94.19	gold quality
quadriceps femoris	UBERON:0001377	94.10	gold quality
adipose tissue	UBERON:0001013	93.96	gold quality
subcutaneous adipose tissue	UBERON:0002190	93.84	gold quality
skeletal muscle tissue	UBERON:0001134	93.55	gold quality
myocardium	UBERON:0002349	93.00	gold quality
right lobe of liver	UBERON:0001114	92.70	gold quality
muscle tissue	UBERON:0002385	92.69	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	92.51	gold quality
cardiac muscle of right atrium	UBERON:0003379	92.47	silver quality
apex of heart	UBERON:0002098	92.45	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.43	gold quality
parietal pleura	UBERON:0002400	92.37	gold quality
omental fat pad	UBERON:0010414	92.18	gold quality
peritoneum	UBERON:0002358	92.16	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.59

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

115 targeting C19orf12, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
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-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-3119	99.92	71.34	2390

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 25)

• orphan mitochondrial protein c19orf12 absence causes a distinct clinical subtype of neurodegeneration with brain iron accumulation (PMID:21981780)
• Sequence analysis of C19orf12 revealed a novel mutation, p.Gly66del, in patients with neurodegeneration with brain iron accumulation mimicking juvenile amyotrophic lateral sclerosis. (PMID:22584950)
• Mutations in the c19orf12 gene encoding a mitochondrial protein of unknown function were identified in patients suffering from Neurodegeneration with brain iron accumulation. (PMID:22691760)
• This study identified 3 patients carrying novel mutations in the C19orf12 gene in patients with neurodegeneration with brain iron accumulation. (PMID:22704260)
• Mutations in both PANK2 and C19orf12 contributed significantly to neurodegeneration with brain iron accumulation in the Iranian patients (PMID:23166001)
• Subsequent testing detected compound heterozygous mutations in c19orf12 consistent with mitochondrial membrane protein-associated neurodegeneration (PMID:23494994)
• Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12. (PMID:23857908)
• Mutations in PANK2 and CoASY lead, respectively, to PKAN and CoPAN forms of Neurodegeneration with brain iron accumulation . Mutations in PLA2G6 lead to PLAN. Mutations in C19orf12 lead to MPAN (PMID:25668476)
• In several families with neurodegeneration with brain iron accumulation, novel mutations were found in the C19orf12 gene. (PMID:25962551)
• Two Turkish sisters with Behr syndrome with homozygous C19ORF12 mutation (PMID:26187298)
• Data indicate two novel homozygous mutations (one frameshift and one missense mutation) detected in CYP7B1 (SPG5A), while no disease-causing mutation was identified for PNPLA6 (SPG39) and C19orf12 (SPG43). (PMID:26714052)
• This study shown neurodegeneration associated with mutations in C19orf12 in the periventricular region. (PMID:28347614)
• The C19orf12 p.Thr11Met mutation is frequent among adult Turkish patients with mitochondrial membrane protein associated neurodegeneration. (PMID:28347615)
• Its mutations are not found in Iranian Parkinson’s disease patients. (PMID:28365006)
• This study showed that C19orf19 genes account for disease of patients diagnosed with an Neurodegeneration with brain iron accumulation disorder. (PMID:29325618)
• and justification for screening C19orf12 was known contribution of mitochondrial dysfunction to ALS etiology (PMID:30553531)
• Brain iron and metabolic abnormalities in C19orf12 mutation carriers: A 7.0 tesla MRI study in mitochondrial membrane protein-associated neurodegeneration. (PMID:31518459)
• pathogenic mutation in C19ORF12 gene (exon2, c.2327C>T, p.P776L) was identified from the patients according to the American College of Medical Genetics and Genomics (ACMG) guideline (PMID:31607023)
• Is there heart disease in cases of neurodegeneration associated with mutations in C19orf12? (PMID:32932022)
• Dominant mitochondrial membrane protein-associated neurodegeneration (MPAN) variants cluster within a specific C19orf12 isoform. (PMID:33260061)
• SPG43 and ALS-like syndrome in the same family due to compound heterozygous mutations of the C19orf12 gene: a case description and brief review. (PMID:33394258)
• C19orf12 ablation causes ferroptosis in mitochondrial membrane protein-associated with neurodegeneration. (PMID:35182730)
• Two cases with mitochondrial membrane protein-associated neurodegeneration: genetic features and long-term clinical follow-up. (PMID:35188090)
• A novel C19orf12 frameshift mutation in a MPAN pedigree impairs mitochondrial function and connectivity leading to neurodegeneration. (PMID:36863113)
• A novel C19ORF12 mutation in two MPAN sisters treated with deferiprone. (PMID:37004026)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	C18H19orf12	ENSDARG00000058857
danio_rerio	C18H19orf12	ENSDARG00000102929
danio_rerio	C18H19orf12	ENSDARG00000104856
danio_rerio	C18H19orf12	ENSDARG00000105232
mus_musculus	1600014C10Rik	ENSMUSG00000054676
rattus_norvegicus	C1h19orf12	ENSRNOG00000014966
drosophila_melanogaster	CG3740	FBGN0023530

Protein

Protein identifiers

Protein C19orf12 — Q9NSK7 (reviewed: Q9NSK7)

All UniProt accessions (4): A0A8C8PZE2, Q9NSK7, F8W6J3, K7EPS8

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Mitochondrion. Mitochondrion membrane. Endoplasmic reticulum. Cytoplasm. Cytosol.

Disease relevance. Neurodegeneration with brain iron accumulation 4 (NBIA4) [MIM:614298] A neurodegenerative disorder associated with iron accumulation in the brain, primarily in the basal ganglia. NBIA4 results in speech difficulty, extrapyramidal signs, oromandibular and generalized dystonia, and parkinsonism. Most patients have progressive involvement of the corticospinal tract, with spasticity, hyperreflexia, and extensor plantar responses. The disease is caused by variants affecting the gene represented in this entry. Spastic paraplegia 43, autosomal recessive (SPG43) [MIM:615043] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SP43 is characterized by childhood onset of progressive spasticity affecting the lower and upper limbs. The disease is caused by variants affecting the gene represented in this entry.

Induction. Up-regulated during adipocyte differentiation in an in vitro preadipocyte differentiation model.

Similarity. Belongs to the C19orf12 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9NSK7-4	1	yes
Q9NSK7-1	4
Q9NSK7-2	2
Q9NSK7-3	3

RefSeq proteins (7): NP_001026896, NP_001242975, NP_001242976, NP_001269858, NP_001269859, NP_001269860, NP_113636* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR033369	C19orf12	Family

Pfam: PF20721

UniProt features (25 total): sequence variant 19, splice variant 4, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NSK7-F1	59.50	0.00

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 308 (showing top): GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_MITOCHONDRIAL_CALCIUM_ION_HOMEOSTASIS, KOYAMA_SEMA3B_TARGETS_UP, GOCC_MITOCHONDRIAL_ENVELOPE, DING_LUNG_CANCER_EXPRESSION_BY_COPY_NUMBER, GOBP_MONOATOMIC_ION_HOMEOSTASIS, MEDINA_SMARCA4_TARGETS, ZHAN_MULTIPLE_MYELOMA_CD1_AND_CD2_DN, GOBP_HOMEOSTATIC_PROCESS, GOBP_CHEMICAL_HOMEOSTASIS, BOCHKIS_FOXA2_TARGETS, VANASSE_BCL2_TARGETS_DN, MEISSNER_NPC_HCP_WITH_H3K4ME2, GOCC_ORGANELLE_ENVELOPE, MODULE_212

GO Biological Process (4): autophagy (GO:0006914), apoptotic process (GO:0006915), response to oxidative stress (GO:0006979), mitochondrial calcium ion homeostasis (GO:0051560)

GO Molecular Function (0):

GO Cellular Component (6): mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), mitochondrial membrane (GO:0031966), cytoplasm (GO:0005737), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
cellular anatomical structure	3
mitochondrion	2
intracellular membrane-bounded organelle	2
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
response to stress	1
intracellular calcium ion homeostasis	1
endomembrane system	1
mitochondrial envelope	1
organelle membrane	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

578 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
C19orf12	FA2H	Q7L5A8	853
C19orf12	PANK2	Q9BZ23	811
C19orf12	PLA2G6	O60733	810
C19orf12	ATP13A2	Q9NQ11	782
C19orf12	DCAF17	Q5H9S7	772
C19orf12	WDR45	Q9Y484	738
C19orf12	COASY	Q13057	722
C19orf12	DDHD1	Q8NEL9	656
C19orf12	FTL	P02792	595
C19orf12	SPG11	Q96JI7	581
C19orf12	GBA2	Q9HCG7	581
C19orf12	DDHD2	O94830	581
C19orf12	MTRFR	Q9H3J6	544
C19orf12	PNPLA6	Q8IY17	513
C19orf12	GTPBP2	Q9BX10	483

IntAct

3 interactions, top by confidence:

A	B	Type	Score
gltD1	C19orf12	psi-mi:“MI:0915”(physical association)	0.000
C19orf12	IKBKG	psi-mi:“MI:0407”(direct interaction)	0.000

BioGRID (3): C19orf12 (Affinity Capture-RNA), C19orf12 (Reconstituted Complex), APP (Reconstituted Complex)

ESM2 similar proteins: A4IFL0, B1H3B1, D3ZLY0, D3ZXD8, E1BD52, E1BWM5, F1N5S9, O14925, O35093, O35094, O43615, P00130, Q08DM5, Q0VCK9, Q28851, Q2KHV4, Q3B8P0, Q4RY26, Q58EA0, Q5BJS4, Q5R5H4, Q5R9K4, Q5RDD0, Q5RI15, Q5SRD1, Q5XH94, Q5XIA8, Q5XJY4, Q68EQ9, Q6DFJ3, Q6DH87, Q6INE8, Q6INU6, Q6NYY9, Q6P4H8, Q7YRC0, Q864V5, Q8IVP5, Q8MJN0, Q91ZQ0

Diamond homologs: Q08DM5, Q1L990, Q6DJ35, Q8WUR0, Q9NSK7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	12
Uncertain significance	174
Likely benign	69
Benign	40

Top pathogenic / likely-pathogenic (26)

Variant ID	HGVS	Classification
1027432	NM_031448.6(C19orf12):c.403dup (p.Ala135fs)	Pathogenic
1188836	NM_031448.6(C19orf12):c.182dup (p.Leu61fs)	Pathogenic
210552	NM_031448.6(C19orf12):c.225_226delinsTGGAGGAACAGT (p.Gln75fs)	Pathogenic
2577335	NM_031448.6(C19orf12):c.267del (p.Phe89fs)	Pathogenic
31626	NM_031448.6(C19orf12):c.362T>A (p.Leu121Gln)	Pathogenic
3362869	NM_031448.6(C19orf12):c.139G>A (p.Gly47Ser)	Pathogenic
3376956	NM_031448.6(C19orf12):c.302G>A (p.Trp101Ter)	Pathogenic
3897647	NM_031448.6(C19orf12):c.211A>T (p.Lys71Ter)	Pathogenic
3897648	NM_031448.6(C19orf12):c.246del (p.Ala83fs)	Pathogenic
3897650	NM_031448.6(C19orf12):c.245del (p.Pro82fs)	Pathogenic
3897672	NM_031448.6(C19orf12):c.271G>T (p.Glu91Ter)	Pathogenic
617482	NM_031448.6(C19orf12):c.-10G>C	Pathogenic
636274	NM_031448.6(C19orf12):c.232_233del (p.Met78fs)	Pathogenic
636275	NM_031448.6(C19orf12):c.194_204del (p.Met65fs)	Pathogenic
1332802	NM_031448.6(C19orf12):c.152T>C (p.Leu51Pro)	Likely pathogenic
153639	GRCh38/hg38 19q12-13.11(chr19:29051888-31967596)x1	Likely pathogenic
2438779	NM_031448.6(C19orf12):c.210del (p.Phe70fs)	Likely pathogenic
2584972	NM_031448.6(C19orf12):c.36_40del (p.Cys13fs)	Likely pathogenic
3362870	NM_031448.6(C19orf12):c.-10-1G>A	Likely pathogenic
3703741	NM_031448.6(C19orf12):c.161-2A>T	Likely pathogenic
3897649	NM_031448.6(C19orf12):c.262C>T (p.Leu88Phe)	Likely pathogenic
402183	NM_031448.6(C19orf12):c.161G>T (p.Gly54Val)	Likely pathogenic
4081216	NM_031448.6(C19orf12):c.224_234del (p.Gln75fs)	Likely pathogenic
443316	GRCh37/hg19 19q12(chr19:30112378-31939682)x3	Likely pathogenic
982027	NM_031448.6(C19orf12):c.240_241dup (p.Pro81fs)	Likely pathogenic
987392	NM_031448.6(C19orf12):c.26T>G (p.Met9Arg)	Likely pathogenic

SpliceAI

841 predictions. Top by Δscore:

Variant	Effect	Δscore
19:29702723:A:AC	donor_gain	1.0000
19:29702724:C:CC	donor_gain	1.0000
19:29702973:CCCCC:C	acceptor_gain	0.9800
19:29702974:CCCC:C	acceptor_gain	0.9800
19:29702974:CCCCC:C	acceptor_gain	0.9800
19:29702975:CCC:C	acceptor_gain	0.9800
19:29702975:CCCC:C	acceptor_gain	0.9800
19:29702976:CCC:C	acceptor_gain	0.9800
19:29708327:C:A	donor_gain	0.9800
19:29708428:G:T	acceptor_gain	0.9800
19:29713465:CAGAT:C	acceptor_gain	0.9800
19:29713469:T:TC	acceptor_gain	0.9700
19:29715598:C:A	donor_gain	0.9700
19:29715722:T:TA	donor_gain	0.9700
19:29702743:T:TA	donor_gain	0.9600
19:29708247:CACT:C	donor_loss	0.9600
19:29708248:ACTT:A	donor_loss	0.9600
19:29708249:CTTAC:C	donor_loss	0.9600
19:29708250:T:TC	donor_loss	0.9600
19:29708251:T:TC	donor_loss	0.9600
19:29708252:A:T	donor_loss	0.9600
19:29708427:C:CT	acceptor_gain	0.9600
19:29708246:GCACT:G	donor_loss	0.9500
19:29708420:GGGCC:G	acceptor_loss	0.9500
19:29708422:GCC:G	acceptor_loss	0.9500
19:29708423:CCTTC:C	acceptor_loss	0.9500
19:29708424:C:CG	acceptor_loss	0.9500
19:29708425:T:G	acceptor_loss	0.9500
19:29715602:C:A	donor_gain	0.9400
19:29702740:AGCT:A	donor_gain	0.9300

AlphaMissense

909 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:29702920:A:T	V84D	0.976
19:29708259:G:T	A63D	0.970
19:29702911:A:G	I87T	0.969
19:29702928:A:C	F81L	0.969
19:29702928:A:T	F81L	0.969
19:29702930:A:G	F81L	0.969
19:29702899:A:G	L91P	0.968
19:29702806:A:T	V122D	0.967
19:29702837:A:G	W112R	0.964
19:29702837:A:T	W112R	0.964
19:29702818:A:G	L118P	0.962
19:29708307:C:T	G47E	0.959
19:29702776:A:G	L132P	0.958
19:29702971:G:T	A67D	0.958
19:29708289:C:T	G53E	0.958
19:29708265:C:T	G61E	0.956
19:29708292:A:T	V52D	0.956
19:29708298:G:T	A50D	0.956
19:29702965:C:T	G69E	0.955
19:29702968:A:T	V68D	0.955
19:29702977:C:T	G65E	0.955
19:29702911:A:C	I87S	0.952
19:29702963:C:G	G70R	0.951
19:29702963:C:T	G70R	0.951
19:29702962:C:T	G70E	0.947
19:29702752:A:T	V140D	0.946
19:29708256:A:T	V64D	0.945
19:29708319:G:T	A43D	0.944
19:29708352:A:G	M32T	0.943
19:29702875:A:G	L99P	0.941

dbSNP variants (sampled 300 via entrez): RS1000187541 (19:29708809 A>T), RS1000254435 (19:29704792 T>C), RS1000391434 (19:29703401 G>A,T), RS1000408134 (19:29717104 C>A,G), RS1000465056 (19:29703135 T>C,G), RS1000539367 (19:29715368 G>A), RS1000644177 (19:29709101 C>T), RS1000689182 (19:29699321 A>T), RS1000725078 (19:29704436 C>A), RS1000921350 (19:29710147 G>A), RS1000942011 (19:29715199 C>A,G), RS1000976276 (19:29699349 G>A), RS1001434 (19:29714541 C>T), RS1001588467 (19:29699694 C>G), RS1001692198 (19:29700673 C>T)

Disease associations

OMIM: gene MIM:614297 | disease phenotypes: MIM:615043, MIM:108600, MIM:614298, MIM:303350, MIM:234200, MIM:270800, MIM:610217, MIM:162200

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodegeneration with brain iron accumulation 4	Definitive	Semidominant
hereditary spastic paraplegia 43	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
neurodegeneration with brain iron accumulation 4	Definitive	AR
neurodegeneration with brain iron accumulation 4	Moderate	AD

Mondo (11): hereditary spastic paraplegia 43 (MONDO:0014024), spastic ataxia (MONDO:0017845), neurodegeneration with brain iron accumulation 4 (MONDO:0013674), hereditary spastic paraplegia (MONDO:0019064), neurodegenerative disease (MONDO:0005559), neurodegeneration with brain iron accumulation (MONDO:0018307), dystonic disorder (MONDO:0003441), hereditary spastic paraplegia 5A (MONDO:0010047), intellectual disability (MONDO:0001071), neurodegeneration with brain iron accumulation 2B (MONDO:0012444), neurofibromatosis type 1 (MONDO:0018975)

Orphanet (9): Autosomal recessive spastic paraplegia type 43 (Orphanet:320370), Spastic ataxia (Orphanet:316226), Mitochondrial membrane protein-associated neurodegeneration (Orphanet:289560), Hereditary spastic paraplegia (Orphanet:685), Neurodegeneration with brain iron accumulation (Orphanet:385), Autosomal recessive spastic paraplegia type 5A (Orphanet:100986), Infantile neuroaxonal dystrophy (Orphanet:35069), Neurofibromatosis type 1 (Orphanet:636), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

48 total (30 of 48 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000529	Progressive visual loss
HP:0000648	Optic atrophy
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000726	Dementia
HP:0000750	Delayed speech and language development
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001258	Spastic paraplegia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001300	Parkinsonism
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001761	Pes cavus
HP:0002071	Abnormality of extrapyramidal motor function
HP:0002180	Neurodegeneration
HP:0002366	Abnormal lower motor neuron morphology
HP:0002454	Eye of the tiger anomaly of globus pallidus
HP:0002460	Distal muscle weakness
HP:0002505	Loss of ambulation
HP:0002936	Distal sensory impairment

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST003487_5	Response to fenofibrate (total cholesterol levels)	9.000000e-06
GCST005845_11	Heart rate increase in response to exercise	1.000000e-09
GCST005848_7	Heart rate response to recovery post exercise (50 sec)	1.000000e-09
GCST005849_9	Heart rate response to recovery post exercise (40 sec)	4.000000e-09
GCST005951_21	Body mass index	4.000000e-09
GCST008163_621	Height	9.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007806	total cholesterol change measurement
EFO:0009184	heart rate response to exercise
EFO:0009185	heart rate response to recovery post exercise
EFO:0004340	body mass index

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D020821	Dystonic Disorders	C10.228.662.300
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D019636	Neurodegenerative Diseases	C10.574
D009456	Neurofibromatosis 1	C04.557.580.600.580.590.650; C04.700.631.650; C10.562.600.500; C10.574.500.549.400; C10.668.829.675; C16.320.400.560.400; C16.320.700.633.650
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
C538421	Neurodegeneration with brain iron accumulation (NBIA) (supp.)
C564815	Spastic Ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Tetrachlorodibenzodioxin	increases expression	2
Valproic Acid	affects expression, decreases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
sodium arsenite	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
perfluorobutanesulfonic acid	decreases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Sunitinib	decreases expression	1
Microplastics	increases abundance, increases expression	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	affects methylation	1
Atrazine	decreases expression	1
Cadmium	increases abundance, increases expression	1
Dexamethasone	increases expression	1
Ozone	affects expression, increases abundance	1
Polystyrenes	increases abundance, increases expression	1
Fenofibrate	increases expression	1
Silver	decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Cyclosporine	decreases expression	1

Cellosaurus cell lines

7 cell lines: 7 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A1MB	IBMS-iPSC-060-04	Induced pluripotent stem cell	Female
CVCL_C9D6	HMGUi004-A	Induced pluripotent stem cell	Female
CVCL_C9D7	FINCBi004-A	Induced pluripotent stem cell	Female
CVCL_E4HF	NENCKIi001-A	Induced pluripotent stem cell	Male
CVCL_E4HG	NENCKIi002-A	Induced pluripotent stem cell	Male
CVCL_E4HH	NENCKIi003-A	Induced pluripotent stem cell	Male
CVCL_E4HI	NENCKIi004-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT01662414	PHASE4	COMPLETED	Effect of Undenatured Cysteine-Rich Whey Protein Isolate (HMS 90®) in Patients With Parkinson’s Disease
NCT04871464	PHASE4	UNKNOWN	Role and Mechanism of Probiotics in Improving Motor Symptoms in Mild to Moderate Parkinson’s Disease
NCT05357612	PHASE4	RECRUITING	Characterization of the Serotonin 2A Receptor Selective PET Tracer [18F]MH.MZ in Patients With Neurodegenerative Diseases
NCT05508789	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Donanemab (LY3002813) in Participants With Early Symptomatic Alzheimer’s Disease (TRAILBLAZER-ALZ 5)
NCT05738486	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Different Donanemab (LY3002813) Dosing Regimens in Adults With Early Alzheimer’s Disease (TRAILBLAZER-ALZ 6)
NCT06111014	PHASE3	TERMINATED	Continuation Study for Latozinemab
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT00001365	PHASE2	COMPLETED	Dextromethorphan for the Treatment of Parkinson’s Disease and Similar Conditions of the Nervous System
NCT00406029	PHASE2	COMPLETED	Dyskinesia in Parkinson’s Disease (Study P04501)
NCT00537017	PHASE2	COMPLETED	Follow Up Safety Study of SCH 420814 in Subjects With Parkinson’s Disease (P05175)
NCT00907283	PHASE2	UNKNOWN	Ferrochelating Treatment in Patients Affected by Neurodegeneration With Brain Iron Accumulation (NBIA)
NCT01518374	PHASE2	COMPLETED	Clinical Evaluation of Florbetapir F 18 (18F-AV-45)
NCT02656498	PHASE2	COMPLETED	[18F]THK-5351 Positron Emission Computed Tomography Study of Normal, Mild Cognitive Impairment, Alzheimer’s Disease and Other Neurodegenerative Disease
NCT03127514	PHASE2	COMPLETED	AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT03538522	PHASE2	COMPLETED	A Double-Blind, Placebo-Controlled Safety and Efficacy Study of NA-831
NCT04838301	PHASE2	RECRUITING	Allopregnanolone Regenerative Therapeutic for Mild Alzheimer’s Disease
NCT04937452	PHASE2	COMPLETED	Dopaminergic Therapy for Frontotemporal Dementia Patients
NCT05318976	PHASE2	COMPLETED	A Study of XPro1595 in Patients With Early Alzheimer’s Disease With Biomarkers of Inflammation
NCT05321498	PHASE2	WITHDRAWN	Study to Assess the Efficacy of XPro1595 in Patients With Mild Cognitive Impairment With Biomarkers of Inflammation
NCT05479981	PHASE2	COMPLETED	Extension of AOC 1001-CS1 (MARINA) Study in Adult Myotonic Dystrophy Type 1 (DM1) Patients
NCT05522387	PHASE2	TERMINATED	An Open-Label Extension of XPro1595 in Patients With Alzheimer’s Disease
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT00316797	PHASE1	COMPLETED	Biodistribution and Safety of a Radiopharmaceutical in Healthy Subjects
NCT01758510	PHASE1	COMPLETED	Safety Study of HLA-haplo Matched Allogenic Bone Marrow Derived Stem Cell Treatment in Amyotrophic Lateral Sclerosis
NCT02267434	PHASE1	COMPLETED	Study Assessing Tolerability and Safety of AFFITOPE® PD03A in Patients With Early Parkinson’s Disease
NCT02270489	PHASE1	COMPLETED	Study Assessing Safety and Therapeutic Activity of AFFITOPE® PD01A and PD03A in Patients With Early MSA
NCT03065192	PHASE1	COMPLETED	Safety and Efficacy Study of VY-AADC01 for Advanced Parkinson’s Disease
NCT04578028	PHASE1	COMPLETED	A First in Human Study to Assess the Safety, Tolerability and Pharmacokinetics of ONO-2808-01 in Healthy Participants
NCT05143463	PHASE1	COMPLETED	A FIH Study to Assess the Safety and Tolerability of NS Intravenous NS101 Infusion
NCT05490576	PHASE1	UNKNOWN	Tau And Connectomics In TES Study
NCT05792163	PHASE1	COMPLETED	A First Time in Human Study of SNP318 as a Treatment for Neurodegenerative Diseases Including Alzheimer’s Disease
NCT07232147	PHASE1	NOT_YET_RECRUITING	Clinical Research on Stem Cell Therapy for Parkinson’s Disease
NCT05678790	Not specified	COMPLETED	Mitochondrial Membrane Protein Neurodegeneration (MPAN)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT04297891	Not specified	UNKNOWN	Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias
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)