FOLR2

Chr 11

folate receptor beta

Also known as: BETA-HFR, FBP, FBP/PL-1, FR-BETA, FR-P3, FRbeta

NCBI Gene: 2350 ENSG00000165457 UniProt: P14207 OMIM: 136425

The protein binds folate and reduced folic acid derivatives with high affinity and mediates cellular delivery of 5-methyltetrahydrofolate through pH-dependent endocytosis and release mechanisms. FOLR2 mutations cause autosomal recessive cerebral folate deficiency, which presents in infancy with developmental regression, seizures, and movement disorders. The gene shows tolerance to loss-of-function variation (LOEUF 1.424), suggesting that complete loss of function may be required for disease manifestation.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a member of the folate receptor (FOLR) family, and these genes exist in a cluster on chromosome 11. Members of this gene family have a high affinity for folic acid and for several reduced folic acid derivatives, and they mediate delivery of 5-methyltetrahydrofolate to the interior of cells. This protein has a 68% and 79% sequence homology with the FOLR1 and FOLR3 proteins, respectively. Although this protein was originally thought to be specific to placenta, it can also exist in other tissues, and it may play a role in the transport of methotrexate in synovial macrophages in rheumatoid arthritis patients. Multiple transcript variants that encode the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.42

LOEUF

GOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.42LOEUF

pLI 0.000

Z-score 0.56

OE 0.82 (0.49–1.42)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.12Z-score

OE missense 0.97 (0.85–1.11)

145 obs / 149.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.82 (0.49–1.42)

0≤0.351.4

Missense OE?0.97 (0.85–1.11)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 9 / 11.0Missense obs/exp: 145 / 149.2Syn Z: 0.19

Background carrier burden — how many people carry a rare variant somewhere in FOLR2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 150

322 rare PASS variants

Rare truncating (LoF)

1 in 2,000

66 rare PASS variants

Rare synonymous (reference)

1 in 530

127 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FOLR2. 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 240	1 in 2,200
South Asian	~43k	1 in 110	1 in 1,400
Remaining (unassigned)	~30k	1 in 100	1 in 1,700
European (Finnish)	~27k	1 in 330	≈ 1 in 8,900
Admixed American	~22k	1 in 120	1 in 3,700
African / African American	~21k	1 in 110	1 in 1,300
East Asian	~20k	1 in 170	1 in 860
Ashkenazi Jewish	~13k	1 in 340	1 in 1,300
Middle Eastern	~2,884	1 in 90	≈ 1 in 960

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 ↓