FLVCR2

Chr 14AR

FLVCR choline and putative heme transporter 2

Also known as: C14orf58, CCT, EPV, FLVCRL14q, MFSD7C, PVHH, SLC49A2, SLC49A5

NCBI Gene: 55640 ENSG00000119686 UniProt: Q9UPI3 OMIM: 610865

This gene encodes a choline transporter that mediates choline uptake across the blood-brain barrier, which is critical for brain development, and also functions as a heme transporter involved in mitochondrial respiration and ATP synthesis. Mutations cause proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome, a severe developmental brain disorder affecting vascular development and resulting in fluid-filled brain cavities. The condition follows autosomal recessive inheritance and FLVCR2 is highly intolerant to loss-of-function mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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.[provided by RefSeq, Aug 2010]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.931 OMIM phenotype

Clinical Summary— FLVCR2

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Gene-Disease Validity (ClinGen)

Fowler syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

21 unique Pathogenic / Likely Pathogenic· 131 VUS of 275 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.93LOEUF

pLI 0.000

Z-score 1.82

OE 0.57 (0.37–0.93)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.06Z-score

OE missense 0.99 (0.90–1.09)

293 obs / 296.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.57 (0.37–0.93)

0≤0.351.4

Missense OE?0.99 (0.90–1.09)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 12 / 21.0Missense obs/exp: 293 / 296.1Syn Z: -0.05

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveFLVCR2-related proliferative vasculopathy and hydraencephaly-hydrocephaly syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.78top 25%

GOF

0.81top 10%

LOF

0.2091th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

275 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13

Likely Pathogenic8

VUS131

Likely Benign81

Benign30

Conflicting7

Pathogenic

Likely Pathogenic

131

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	8	5	0	0	13
Likely Pathogenic	6	2	0	0	8
VUS	1	100	26	4	131
Likely Benign	0	8	30	43	81
Benign	0	2	25	3	30
Conflicting	—				7
Total	15	117	81	50	270

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

14 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap FLVCR2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →