FLT1

Chr 13

fms related receptor tyrosine kinase 1

Also known as: FLT, FLT-1, VEGFR-1, VEGFR1

NCBI Gene: 2321 ENSG00000102755 UniProt: P17948

This gene encodes VEGFR-1, a receptor tyrosine kinase that binds VEGF-A, VEGF-B, and placental growth factor to regulate angiogenesis, vasculogenesis, and endothelial cell survival during embryonic development and in adulthood. Mutations cause autosomal dominant retinal arterial macroaneurysm with supravalvular pulmonic stenosis, a condition affecting the cardiovascular and ocular systems. The gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.25), indicating that most loss-of-function mutations are likely pathogenic.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of the vascular endothelial growth factor receptor (VEGFR) family. VEGFR family members are receptor tyrosine kinases (RTKs) which contain an extracellular ligand-binding region with seven immunoglobulin (Ig)-like domains, a transmembrane segment, and a tyrosine kinase (TK) domain within the cytoplasmic domain. This protein binds to VEGFR-A, VEGFR-B and placental growth factor and plays an important role in angiogenesis and vasculogenesis. Expression of this receptor is found in vascular endothelial cells, placental trophoblast cells and peripheral blood monocytes. Multiple transcript variants encoding different isoforms have been found for this gene. Isoforms include a full-length transmembrane receptor isoform and shortened, soluble isoforms. The soluble isoforms are associated with the onset of pre-eclampsia.[provided by RefSeq, May 2009]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

154

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.25

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.25LOEUF

pLI 1.000

Z-score 6.57

OE 0.15 (0.09–0.25)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.45Z-score

OE missense 0.85 (0.79–0.91)

611 obs / 720.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.15 (0.09–0.25)

0≤0.351.4

Missense OE?0.85 (0.79–0.91)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 10 / 68.9Missense obs/exp: 611 / 720.9Syn Z: -0.08

Background carrier burden — how many people carry a rare variant somewhere in FLT1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 48

1,510 rare PASS variants

Rare truncating (LoF)

1 in 1,500

132 rare PASS variants

Rare synonymous (reference)

1 in 63

674 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FLT1. 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 60	1 in 1,900
South Asian	~43k	1 in 39	1 in 950
Remaining (unassigned)	~30k	1 in 42	1 in 1,500
European (Finnish)	~27k	1 in 160	1 in 4,400
Admixed American	~22k	1 in 49	1 in 1,200
African / African American	~21k	1 in 31	1 in 1,100
East Asian	~20k	1 in 35	1 in 1,200
Ashkenazi Jewish	~13k	1 in 130	1 in 1,600
Middle Eastern	~2,884	1 in 46	≈ 1 in 910

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): 25 of 30 coding exons well covered in gnomAD exomes; exons 2, 11, 22, 26, 28 marginal. Genomes: all 30.? see exons ↓