FOLR1

Chr 11AR

folate receptor alpha

Also known as: FBP, FOLR, FR-alpha, FRalpha, NCFTD

NCBI Gene: 2348 ENSG00000110195 UniProt: P15328 OMIM: 136430

The encoded protein binds folate and reduced folic acid derivatives and mediates cellular uptake of 5-methyltetrahydrofolate through receptor-mediated endocytosis. Mutations cause neurodegeneration due to cerebral folate transport deficiency, inherited in an autosomal recessive pattern. This condition impairs folate transport across the blood-brain barrier, leading to progressive neurological deterioration despite normal systemic folate levels.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a member of the folate receptor family. Members of this gene family bind folic acid and its reduced derivatives, and transport 5-methyltetrahydrofolate into cells. This gene product is a secreted protein that either anchors to membranes via a glycosyl-phosphatidylinositol linkage or exists in a soluble form. Mutations in this gene have been associated with neurodegeneration due to cerebral folate transport deficiency. Due to the presence of two promoters, multiple transcription start sites, and alternative splicing, multiple transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Neurodegeneration due to cerebral folate transport deficiencyMIM #613068

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · neurodegenerative syndrome due to cerebral folate transport deficiency · AR · ClinGen 2017

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

115

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.65

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — FOLR1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.65LOEUF

pLI 0.126

Z-score 2.48

OE 0.29 (0.14–0.65)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.67Z-score

OE missense 0.84 (0.72–0.98)

117 obs / 139.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.29 (0.14–0.65)

0≤0.351.4

Missense OE?0.84 (0.72–0.98)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 4 / 14.0Missense obs/exp: 117 / 139.4Syn Z: 0.71

Background carrier burden — how many people carry a rare variant somewhere in FOLR1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 290

293 rare PASS variants

Rare truncating (LoF)

1 in 4,100

42 rare PASS variants

Rare synonymous (reference)

1 in 300

113 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FOLR1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 390	1 in 3,500
South Asian	~43k	1 in 220	1 in 8,600
Remaining (unassigned)	~30k	1 in 250	1 in 3,000
European (Finnish)	~27k	1 in 740	1 in 1,200
Admixed American	~22k	1 in 290	none seen
African / African American	~21k	1 in 170	1 in 1,900
East Asian	~20k	1 in 500	≈ 1 in 6,600
Ashkenazi Jewish	~13k	1 in 590	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 260	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 4 coding exons well covered in gnomAD exomes and genomes.? see exons ↓