FLVCR2

Summary

FLVCR2 (FLVCR choline and putative heme transporter 2, HGNC:20105) is a protein-coding gene on chromosome 14q24.3, encoding Choline/ethanolamine transporter FLVCR2 (Q9UPI3). Choline uniporter that specifically mediates choline uptake at the blood-brain-barrier.

This gene encodes a member of the major facilitator superfamily. The encoded transmembrane protein is a calcium transporter. Unlike the related protein feline leukemia virus subgroup C receptor 1, the protein encoded by this locus does not bind to feline leukemia virus subgroup C envelope protein. The encoded protein may play a role in development of brain vascular endothelial cells, as mutations at this locus have been associated with proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome. Alternatively spliced transcript variants have been described.

Source: NCBI Gene 55640 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Fowler syndrome (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 264 total — 12 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 24
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_017791

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20105
Approved symbol	FLVCR2
Name	FLVCR choline and putative heme transporter 2
Location	14q24.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20371, MFSD7C, SLC49A2, CCT
Ensembl gene	ENSG00000119686
Ensembl biotype	protein_coding
OMIM	610865
Entrez	55640

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 17 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000238667, ENST00000539311, ENST00000553341, ENST00000553587, ENST00000554496, ENST00000554580, ENST00000555027, ENST00000555058, ENST00000555385, ENST00000556241, ENST00000556409, ENST00000556745, ENST00000556856, ENST00000852182, ENST00000852184, ENST00000852186, ENST00000852188, ENST00000852190, ENST00000852192, ENST00000852195, ENST00000943496, ENST00000943497

RefSeq mRNA: 2 — MANE Select: NM_017791 NM_001195283, NM_017791

CCDS: CCDS55933, CCDS9844

Canonical transcript exons

ENST00000238667 — 10 exons

Exon	Start	End
ENSE00000808369	75578620	75579641
ENSE00000808375	75640955	75641060
ENSE00000808378	75646401	75648167
ENSE00003466887	75641182	75641293
ENSE00003495822	75633629	75633696
ENSE00003565341	75622079	75622220
ENSE00003577535	75639352	75639462
ENSE00003610840	75624612	75624752
ENSE00003681307	75634910	75635013
ENSE00003786466	75641843	75641898

Expression profiles

Bgee: expression breadth ubiquitous, 211 present calls, max score 90.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.7235 / max 89.8211, expressed in 999 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
140691	2.7067	886
140692	1.7361	507
140693	0.0878	43
140696	0.0872	37
140695	0.0275	14
140697	0.0268	11
207302	0.0192	8
207303	0.0178	6
140694	0.0144	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	90.83	gold quality
tibial nerve	UBERON:0001323	90.10	gold quality
monocyte	CL:0000576	89.66	gold quality
mononuclear cell	CL:0000842	89.57	gold quality
leukocyte	CL:0000738	88.94	gold quality
sperm	CL:0000019	87.91	gold quality
right testis	UBERON:0004534	87.20	gold quality
left testis	UBERON:0004533	86.95	gold quality
oocyte	CL:0000023	86.93	gold quality
right adrenal gland cortex	UBERON:0035827	86.58	gold quality
left adrenal gland cortex	UBERON:0035825	86.52	gold quality
left adrenal gland	UBERON:0001234	86.42	gold quality
ileal mucosa	UBERON:0000331	86.38	gold quality
right adrenal gland	UBERON:0001233	86.36	gold quality
adrenal gland	UBERON:0002369	85.48	gold quality
right lobe of liver	UBERON:0001114	85.38	gold quality
adrenal cortex	UBERON:0001235	85.32	gold quality
buccal mucosa cell	CL:0002336	85.20	gold quality
pigmented layer of retina	UBERON:0001782	85.16	gold quality
testis	UBERON:0000473	85.14	gold quality
mucosa of transverse colon	UBERON:0004991	84.77	gold quality
male germ cell	CL:0000015	84.68	gold quality
small intestine Peyer’s patch	UBERON:0003454	84.04	gold quality
spleen	UBERON:0002106	84.02	gold quality
small intestine	UBERON:0002108	83.41	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.38	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.04	gold quality
granulocyte	CL:0000094	82.95	gold quality
sural nerve	UBERON:0015488	82.95	gold quality
duodenum	UBERON:0002114	82.85	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.36

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

86 targeting FLVCR2, 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-8485	100.00	77.57	4731
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 13)

• Direct sequencing of candidate genes within the target interval in chromosome 14q24.3 revealed five different germline mutations in FLVCR2 in five families with Fowler syndrome. (PMID:20206334)
• High-throughput sequence data identified mutations and a large deletion in the FLVCR2 gene casuing lethal cerebral vasculopathy. (PMID:20690116)
• Results report the cellular function of FLVCR2 as an importer of heme. (PMID:20823265)
• FLVCR2 mutation is associated with Hydranencephaly. (PMID:25131804)
• Mutations in FLVCR2 associated with Fowler syndrome and survival beyond infancy (PMID:25677735)
• Mutations in FLVCR2 gene are responsible for Proliferative vasculopathy and Hydranencephaly-hydrocephaly syndrome. FLVCR2 transporter is gatekeeper for the controlled entry of calcium into cell, and involves the regulation of calcium metabolism. (PMID:25906927)
• Expanding the clinical spectrum of Fowler syndrome: Three siblings with survival into adulthood and systematic review of the literature. (PMID:32333401)
• Variability of non-lethal Fowler syndrome phenotype associated with FLVCR2 variants. (PMID:32901920)
• MFSD7C switches mitochondrial ATP synthesis to thermogenesis in response to heme. (PMID:32973183)
• MFSD7c functions as a transporter of choline at the blood-brain barrier. (PMID:38302740)
• Structural and molecular basis of choline uptake into the brain by FLVCR2. (PMID:38693257)
• Molecular mechanism of choline and ethanolamine transport in humans. (PMID:38778100)
• MFSD7C protects hemolysis-induced lung impairments by inhibiting ferroptosis. (PMID:39300060)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	flvcr2b	ENSDARG00000031506
danio_rerio	flvcr2a	ENSDARG00000038957
mus_musculus	Flvcr2	ENSMUSG00000034258
rattus_norvegicus	Flvcr2	ENSRNOG00000008754
drosophila_melanogaster	HisT	FBGN0033196
caenorhabditis_elegans	C09D4.1	WBGENE00015632

Paralogs (4): SLC49A4 (ENSG00000138463), FLVCR1 (ENSG00000162769), SLC49A3 (ENSG00000169026), CFAP276 (ENSG00000179902)

Protein

Protein identifiers

Choline/ethanolamine transporter FLVCR2 — Q9UPI3 (reviewed: Q9UPI3)

Alternative names: Calcium-chelate transporter, Feline leukemia virus subgroup C receptor-related protein 2, Heme transporter FLVCR2

All UniProt accessions (7): Q9UPI3, G3V391, G3V458, G3V4G2, G3V5P5, G3V5Q8, G3V5Y3

UniProt curated annotations — full annotation on UniProt →

Function. Choline uniporter that specifically mediates choline uptake at the blood-brain-barrier. Responsible for the majority of choline uptake across the blood-brain-barrier from the circulation into the brain. Choline, a nutrient critical for brain development, is a precursor of phosphatidylcholine, as well as betaine. Also mediates transport of ethanolamine. Choline and ethanolamine transport is not coupled with proton transport and is exclusively driven by the choline gradient across the plasma membrane. However, the presence of an inwardly directed proton gradient enhances choline uptake. Also acts as a heme b transporter. Required to regulate mitochondrial respiration processes, ATP synthesis and thermogenesis. At low heme levels, interacts with components of electron transfer chain (ETC) complexes and ATP2A2, leading to ubiquitin-mediated degradation of ATP2A2 and inhibition of thermogenesis. Upon heme binding, dissociates from ETC complexes to allow switching from mitochondrial ATP synthesis to thermogenesis.

Subunit / interactions. Interacts with components of electron transfer chain complexes III, IV and V including CYC1, COXFA4, COX4I1, ATP5PD and ATP5F1C; these interactions occur in the absence of heme and are disrupted upon heme binding. Interacts with ATP2A2; this interaction occurs in the absence of heme and promotes ATP2A2 proteasomal degradation; the complex is dissociated upon heme binding. Interacts with HMOX1; this interaction is potentiated in the presence of heme.

Subcellular location. Cell membrane. Mitochondrion membrane. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in non-hematopoietic tissues, with relative abundant expression in brain, placenta, lung, liver and kidney. Also expressed in hematopoietic tissues (fetal liver, spleen, lymph node, thymus, leukocytes and bone marrow). Found in acidophil cells of the pituitary that secrete growth hormone and prolactin (at protein level).

Disease relevance. Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH) [MIM:225790] A rare prenatally lethal disorder characterized by hydranencephaly, a distinctive glomerular vasculopathy in the central nervous system and retina, and diffuse ischemic lesions of the brain stem, basal ganglia, and spinal cord with calcifications. Hydranencephaly is a condition where the greater portions of the cerebral hemispheres and corpus striatum are replaced by cerebrospinal fluid and glial tissue. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The N-terminus contains histidine-proline motifs involved in heme binding. Can bind 2 to 3 heme molecules.

Similarity. Belongs to the major facilitator superfamily. Feline leukemia virus subgroup C receptor (TC 2.A.1.28.1) family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UPI3-1	1	yes
Q9UPI3-2	2

RefSeq proteins (2): NP_001182212, NP_060261* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011701	MFS	Family
IPR020846	MFS_dom	Domain
IPR036259	MFS_trans_sf	Homologous_superfamily
IPR049680	FLVCR1-2_SLC49-like	Family

Pfam: PF07690

Catalyzed reactions (Rhea), 3 shown:

• ethanolamine(in) = ethanolamine(out) (RHEA:32747)
• choline(out) = choline(in) (RHEA:32751)
• heme b(in) = heme b(out) (RHEA:75443)

UniProt features (92 total): helix 18, sequence variant 14, topological domain 13, transmembrane region 12, repeat 8, binding site 7, mutagenesis site 6, region of interest 3, splice variant 2, sequence conflict 2, turn 2, strand 2, chain 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8QD0	ELECTRON MICROSCOPY	2.8
8QCY	ELECTRON MICROSCOPY	2.9
8QCX	ELECTRON MICROSCOPY	3.1
8QCZ	ELECTRON MICROSCOPY	3.1
9QU4	ELECTRON MICROSCOPY	3.39

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UPI3-F1	81.31	0.56

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 (7): 1–84; 98; 102; 191; 195; 325; 447

Post-translational modifications (1): 515

Mutagenesis-validated functional residues (6):

Position	Phenotype
30–66	loss of heme-binding activity.
102	reduced transport of choline and ethanolamine.
191	reduced transport of choline and ethanolamine.
222	reduced transport of choline and ethanolamine.
325	slightly reduced transport of choline and ethanolamine.
447	reduced transport of choline and ethanolamine.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 244 (showing top): GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_IRON_COORDINATION_ENTITY_TRANSPORT, GOBP_TRANSITION_METAL_ION_TRANSPORT, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GGGTGGRR_PAX4_03, GOBP_IRON_ION_TRANSPORT, SP1_Q2_01, CEBPB_01, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT, chr14q24, GOCC_MITOCHONDRIAL_ENVELOPE, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, ONDER_CDH1_TARGETS_2_UP, SANSOM_APC_TARGETS_DN

GO Biological Process (5): choline transport (GO:0015871), heme export (GO:0097037), transport across blood-brain barrier (GO:0150104), ethanolamine transport (GO:0034229), transmembrane transport (GO:0055085)

GO Molecular Function (5): choline transmembrane transporter activity (GO:0015220), heme transmembrane transporter activity (GO:0015232), heme binding (GO:0020037), ethanolamine transmembrane transporter activity (GO:0034228), transmembrane transporter activity (GO:0022857)

GO Cellular Component (6): endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), membrane (GO:0016020), mitochondrial membrane (GO:0031966), mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
heme transport	2
transmembrane transporter activity	2
organelle membrane	2
cytoplasm	2
intracellular membrane-bounded organelle	2
nitrogen compound transport	1
vascular transport	1
amine transport	1
organic hydroxy compound transport	1
transport	1
cellular process	1
choline transport	1
tetrapyrrole binding	1
amine transmembrane transporter activity	1
alcohol transmembrane transporter activity	1
ethanolamine transport	1
transporter activity	1
transmembrane transport	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
cellular anatomical structure	1
mitochondrion	1
mitochondrial envelope	1
endomembrane system	1

Protein interactions and networks

STRING

696 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FLVCR2	SLC46A1	Q96NT5	596
FLVCR2	HMOX1	P09601	564
FLVCR2	ABCB10	Q9NRK6	541
FLVCR2	ALAS1	P13196	537
FLVCR2	STEAP3	Q658P3	534
FLVCR2	SLC48A1	Q6P1K1	534
FLVCR2	SLC40A1	Q9NP59	519
FLVCR2	HPX	P02790	511
FLVCR2	NCOA4	Q13772	474
FLVCR2	PCBP1	Q15365	473
FLVCR2	FXN	Q16595	460
FLVCR2	FTL	P02792	458
FLVCR2	PPOX	P50336	454
FLVCR2	DHX40	Q8IX18	449
FLVCR2	FBXL5	Q9UKA1	427

IntAct

4 interactions, top by confidence:

A	B	Type	Score
FLVCR2	EPN1	psi-mi:“MI:0915”(physical association)	0.400
FLVCR2	PLPP1	psi-mi:“MI:0914”(association)	0.350

BioGRID (45): FLVCR2 (Affinity Capture-RNA), FLVCR2 (Affinity Capture-RNA), EPN1 (Affinity Capture-MS), EPN1 (Affinity Capture-MS), GSS (Co-fractionation), HINT2 (Co-fractionation), MRPL48 (Co-fractionation), NLN (Co-fractionation), NXF1 (Co-fractionation), PLIN3 (Co-fractionation), RPIA (Co-fractionation), SLC19A3 (Co-fractionation), WARS2 (Co-fractionation), PFAS (Co-fractionation), ABCB1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4ILB2, A0A8M9Q308, A1A4N1, A2CER7, A5D7V7, A8WGF7, B0S5Y3, B2RXV4, B5X4H8, O00400, O00476, O01735, O23596, P30638, P36836, P46029, P60815, Q11073, Q16348, Q28722, Q28FF3, Q503P5, Q5F4B8, Q5RBM3, Q5XGK0, Q63424, Q6AYY8, Q6DDL7, Q6DIT7, Q6GMG6, Q6PB15, Q7Z3Q1, Q84XI3, Q86WB7, Q91X85, Q944P0, Q99808, Q99J27, Q9BZD2, Q9C8X2

Diamond homologs: A0A0R4ILB2, A0A8M9Q308, B2RXV4, O01735, P60815, Q91X85, Q9ES43, Q9N1F2, Q9UPI3, Q9Y5Y0, Q28FF3, Q501I9, Q66H95, Q6GNV7, Q8BFQ6, Q96SL1, Q6UXD7, Q8CE47

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	5
Uncertain significance	127
Likely benign	72
Benign	30

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1087	NM_017791.3(FLVCR2):c.1289C>G (p.Thr430Arg)	Pathogenic
1089	NM_017791.3(FLVCR2):c.1192C>G (p.Leu398Val)	Pathogenic
1091	NM_017791.3(FLVCR2):c.839C>G (p.Pro280Arg)	Pathogenic
1092	NM_017791.3(FLVCR2):c.977C>T (p.Ala326Val)	Pathogenic
1093	NM_017791.3(FLVCR2):c.1341+2T>C	Pathogenic
2227177	NM_017791.3(FLVCR2):c.721_731del (p.Glu241fs)	Pathogenic
30856	NM_017791.3(FLVCR2):c.402C>G (p.Tyr134Ter)	Pathogenic
3363141	NM_017791.3(FLVCR2):c.1101G>A (p.Trp367Ter)	Pathogenic
3663455	NM_017791.3(FLVCR2):c.1057_1060del (p.Ile353fs)	Pathogenic
418732	NM_017791.3(FLVCR2):c.1011del (p.Trp337fs)	Pathogenic
4399389	NM_017791.3(FLVCR2):c.1509+1G>A	Pathogenic
523100	NM_017791.3(FLVCR2):c.1289C>T (p.Thr430Met)	Pathogenic
2991798	NM_017791.3(FLVCR2):c.1124+1G>T	Likely pathogenic
3341082	NM_017791.3(FLVCR2):c.191del (p.Leu64fs)	Likely pathogenic
3699250	NM_017791.3(FLVCR2):c.812-2A>G	Likely pathogenic
4081398	NM_017791.3(FLVCR2):c.1024del	Likely pathogenic
4755688	NM_017791.3(FLVCR2):c.1076T>C (p.Leu359Pro)	Likely pathogenic

SpliceAI

2564 predictions. Top by Δscore:

Variant	Effect	Δscore
14:75579642:G:T	donor_loss	1.0000
14:75622073:CTATA:C	acceptor_loss	1.0000
14:75622074:TATAG:T	acceptor_loss	1.0000
14:75622075:ATAG:A	acceptor_loss	1.0000
14:75622076:T:G	acceptor_gain	1.0000
14:75622076:TAG:T	acceptor_loss	1.0000
14:75622077:A:AG	acceptor_gain	1.0000
14:75622077:AG:A	acceptor_loss	1.0000
14:75622077:AGCTT:A	acceptor_gain	1.0000
14:75622078:G:A	acceptor_loss	1.0000
14:75622078:G:GG	acceptor_gain	1.0000
14:75622078:GC:G	acceptor_gain	1.0000
14:75622078:GCTT:G	acceptor_gain	1.0000
14:75622078:GCTTG:G	acceptor_gain	1.0000
14:75622182:G:GT	donor_gain	1.0000
14:75622221:G:GG	donor_gain	1.0000
14:75640940:T:TA	acceptor_gain	1.0000
14:75640945:T:TA	acceptor_gain	1.0000
14:75641170:AT:A	acceptor_gain	1.0000
14:75641171:T:G	acceptor_gain	1.0000
14:75641171:T:TA	acceptor_gain	1.0000
14:75641177:TCCA:T	acceptor_loss	1.0000
14:75641178:CCAG:C	acceptor_loss	1.0000
14:75641179:CA:C	acceptor_loss	1.0000
14:75641181:GGT:G	acceptor_gain	1.0000
14:75641294:G:GG	donor_gain	1.0000
14:75641294:G:T	donor_loss	1.0000
14:75641295:TGA:T	donor_loss	1.0000
14:75641296:GAG:G	donor_loss	1.0000
14:75641827:A:AG	acceptor_gain	1.0000

AlphaMissense

3433 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:75579588:T:C	F206L	0.999
14:75579590:C:A	F206L	0.999
14:75579590:C:G	F206L	0.999
14:75579585:T:A	W205R	0.998
14:75579585:T:C	W205R	0.998
14:75579613:C:A	A214D	0.996
14:75641005:T:C	L429P	0.996
14:75579246:A:C	S92R	0.995
14:75579248:C:A	S92R	0.995
14:75579248:C:G	S92R	0.995
14:75579577:C:A	A202D	0.995
14:75622082:G:A	G225R	0.995
14:75622082:G:C	G225R	0.995
14:75622083:G:A	G225E	0.995
14:75641868:A:C	R493S	0.995
14:75641868:A:T	R493S	0.995
14:75579589:T:C	F206S	0.994
14:75633641:G:A	G322D	0.994
14:75634938:G:A	G350D	0.994
14:75639461:G:C	G412R	0.994
14:75579276:T:A	W102R	0.993
14:75579276:T:C	W102R	0.993
14:75579455:C:A	N161K	0.993
14:75579455:C:G	N161K	0.993
14:75579588:T:A	F206I	0.993
14:75622089:C:A	A227E	0.993
14:75622095:G:A	G229E	0.993
14:75633629:G:A	G318D	0.993
14:75641867:G:C	R493T	0.993
14:75579483:A:C	S171R	0.992

dbSNP variants (sampled 300 via entrez): RS1000034813 (14:75629499 T>C), RS1000120031 (14:75592244 A>C), RS1000122158 (14:75609561 G>A), RS1000158382 (14:75608666 G>A,T), RS1000209728 (14:75618424 A>C,G), RS1000236405 (14:75634097 T>A), RS1000375726 (14:75596470 A>C), RS1000419146 (14:75640358 T>A), RS1000435343 (14:75604739 T>C), RS1000515054 (14:75609785 G>A), RS1000539744 (14:75636785 T>C), RS1000587000 (14:75634403 G>A), RS1000602573 (14:75616881 A>G), RS1000653752 (14:75603660 G>A), RS1000659397 (14:75609602 G>T)

Disease associations

OMIM: gene MIM:610865 | disease phenotypes: MIM:225790, MIM:609033, MIM:614429

GenCC curated gene-disease

Disease	Classification	Inheritance
Fowler syndrome	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Fowler syndrome	Definitive	AR

Mondo (4): Fowler syndrome (MONDO:0009168), posterior column ataxia-retinitis pigmentosa syndrome (MONDO:0012177), ventricular septal defect (MONDO:0002070), hydrops fetalis (MONDO:0015193)

Orphanet (4): Fowler vasculopathy (Orphanet:221126), Posterior column ataxia-retinitis pigmentosa syndrome (Orphanet:88628), Hydrops fetalis (Orphanet:1041), NON RARE IN EUROPE: Ventricular septal defect (Orphanet:1480)

HPO phenotypes

24 total (26 of 24 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000175	Cleft palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000347	Micrognathia
HP:0000476	Cystic hygroma
HP:0001059	Pterygium
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001274	Agenesis of corpus callosum
HP:0001305	Dandy-Walker malformation
HP:0001321	Cerebellar hypoplasia
HP:0001511	Intrauterine growth retardation
HP:0001561	Polyhydramnios
HP:0001622	Premature birth
HP:0001883	Talipes
HP:0002119	Ventriculomegaly
HP:0002126	Polymicrogyria
HP:0002304	Akinesia
HP:0002324	Hydranencephaly
HP:0002365	Hypoplasia of the brainstem
HP:0003577	Congenital onset
HP:0009004	Hypoplasia of the musculature
HP:0034392	Joint contracture
HP:0001629	Ventricular septal defect
HP:0001789	Hydrops fetalis

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009617_1	LDL cholesterol levels x thiazide or thiazide-like diuretics use interaction	1.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D006345	Heart Septal Defects, Ventricular	C14.240.400.560.540; C14.280.400.560.540; C16.131.240.400.560.540
D015160	Hydrops Fetalis	C12.050.703.277.060.480; C15.378.295.480; C15.378.420.826.100.350; C16.300.060.480; C16.320.365.826.100.350; C20.306.480; C23.888.277.395
C565593	Encephaloclastic Proliferative Vasculopathy (supp.)
C536343	Posterior column ataxia with retinitis pigmentosa (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — SLC49 family of FLVCR-related heme transporters

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	5
Vorinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Estradiol	increases expression, affects cotreatment, decreases expression	2
Cyclosporine	decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
chloroacetaldehyde	increases expression	1
trichostatin A	increases expression	1
sodium bichromate	decreases expression	1
sulforaphane	decreases expression	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
perfluorooctane sulfonic acid	increases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
dorsomorphin	increases expression, affects cotreatment	1
bisphenol S	increases expression	1
jinfukang	increases expression	1
incobotulinumtoxinA	decreases expression	1
gardiquimod	increases expression, decreases reaction	1
NSC 689534	affects binding, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	increases expression	1
Cidofovir	affects expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, decreases expression	1
Cisplatin	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4RG	HuH7-FLVCR2-KO-c1	Cancer cell line	Male
CVCL_D4RH	HuH7-FLVCR2-KO-c5	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02914652	PHASE4	COMPLETED	The Cardiopulmonary Effect of Inhaled Beta-2-agonists on Adult Patients Born With Ventricular Septum Defects.
NCT05688670	PHASE4	COMPLETED	Regional Anesthesia Following Pediatric Cardiac Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00113698	PHASE3	TERMINATED	Angiotensin Converting Enzyme Inhibition in Children With Mitral Regurgitation
NCT05253209	PHASE3	TERMINATED	A Study Evaluating the Efficacy and Safety of IV L-Citrulline for the Prevention of Clinical Sequelae of Acute Lung Injury Induced by Cardiopulmonary Bypass in Pediatric Patients Undergoing Surgery for Congenital Heart Defects
NCT00199771	PHASE2	COMPLETED	Hypertonic Saline Dextran in Pediatric Cardiac Surgery
NCT00556361	PHASE2	COMPLETED	Use of Ketamine Prior to Cardiopulmonary Bypass in Children
NCT00848393	PHASE2	COMPLETED	Measures to Lower the Stress Response in Pediatric Cardiac Surgery
NCT04017975	PHASE2	ACTIVE_NOT_RECRUITING	Optical Tissue Identification for Myocardial Architecture
NCT01825369	PHASE1	WITHDRAWN	Aberrations in Carnitine Homeostasis in Congenital Heart Disease With Increased Pulmonary Blood Flow
NCT01915277	PHASE1	COMPLETED	A Phase I Study of Dexmedetomidine Bolus and Infusion in Corrective Infant Cardiac Surgery: Safety and Pharmacokinetics
NCT02986698	PHASE1	TERMINATED	In Utero Hematopoietic Stem Cell Transplantation for Alpha-thalassemia Major (ATM)
NCT05313984	Not specified	COMPLETED	OptiLUTS Part C: the Development of a Symptom Assessment Tool in Sacral Neuromodulation.
NCT06565572	EARLY_PHASE1	ENROLLING_BY_INVITATION	Antisense Oligonucleotide Treatment for PCARP Disease Due to Mutation in FLVCR1
NCT01120964	PHASE1/PHASE2	COMPLETED	Intravenous L-Citrulline to Treat Children Undergoing Heart Bypass Surgery : Revised Protocol
NCT06298344	EARLY_PHASE1	COMPLETED	The Role of Thiamine After Transcatheter Closure in Children With Left-to-Right Shunt Congenital Heart Disease
NCT00005190	Not specified	COMPLETED	Reproduction and Survival After Cardiac Defect Repair
NCT00005322	Not specified	COMPLETED	Molecular Genetic Epidemiology of Endocardial Cushion Defects - SCOR in Pediatric Cardiovascular Disease
NCT00005546	Not specified	COMPLETED	Molecular Genetic Epidemiology of Three Cardiac Defects -SCOR in Pediatric Cardiovascular Disease
NCT00006272	Not specified	UNKNOWN	Study of Energy Expenditure in Infants With Ventricular Septal Defects
NCT00173186	Not specified	UNKNOWN	Aortic Regurgitation After Surgical Repair of Outlet-Type Ventricular Septal Defect
NCT00229827	Not specified	TERMINATED	Optimal Timing for Repair of Left to Right Shunt Lesions
NCT00390702	Not specified	COMPLETED	Safety and Effectiveness of the Nit-Occlud® Lê VSD Spiral Coil System
NCT00583505	Not specified	NO_LONGER_AVAILABLE	Emergency/Compassionate Use - Membranous VSD Occluder
NCT00583791	Not specified	COMPLETED	Closure of Muscular Ventricular Septal Defects With The AMPLATZER™ Muscular VSD Occluder
NCT00590382	Not specified	APPROVED_FOR_MARKETING	Emergency/Compassionate Use - Muscular VSD Occluder
NCT00647387	Not specified	COMPLETED	Closure of Muscular Ventricular Septal Defects (VSDs) With the AMPLATZER Muscular VSD (MuVSD) Occluder - Post Approval Study
NCT00890799	Not specified	COMPLETED	Transcatheter Closure Versus Surgery of Perimembranous Ventricular Septal Defects
NCT01313832	Not specified	COMPLETED	The Effect of Remote Ischemic Preconditioning on the Ischemic Reperfusion Injury in Infants With Ventricular Septal Defect and Pulmonary Hypertension
NCT01480908	Not specified	COMPLETED	Right Bundle Branch Block After Surgical Closure of Ventricular Septal Defect
NCT02138435	Not specified	COMPLETED	Longterm Outcome After Ventricular Septal Defect Closure
NCT02361008	Not specified	COMPLETED	A Randomized Controlled Trial:Treatments on Infundibular Ventricular Septal Defect
NCT02552485	Not specified	COMPLETED	Evaluation of Latent Pulmonary Arterial Hypertension in Congenital Shunt Lesions
NCT03127748	Not specified	UNKNOWN	Cardiac Function After Transcatheter VSD Closure
NCT03684161	Not specified	COMPLETED	Cardiopulmonary Function in Adults Born With a Ventricular Septal Defect
NCT03941691	Not specified	UNKNOWN	A Trial to Evaluate the Safety and Efficacy of a Fully Degradable Ventricular Septal Defect (VSD) Closure
NCT04417712	Not specified	COMPLETED	Lifetech KONAR MFO Post-Market Clinical Follow-Up Study
NCT04667455	Not specified	COMPLETED	Improving Care for Children With Congenital Heart Disease.
NCT04859036	Not specified	COMPLETED	The Effect of Transcatheter Ventricular Septal Defect Closure on Heart Rate Variability Parameters
NCT05200910	Not specified	COMPLETED	The Effect of Transcatheter VSD Closure on Children’s Appetite, Hormones and Growth