FLRT1

Chr 11

fibronectin leucine rich transmembrane protein 1

Also known as: SPG68

NCBI Gene: 23769 ENSG00000126500 UniProt: Q9NZU1 OMIM: 604806

The encoded protein is a transmembrane receptor that promotes neurite outgrowth through fibroblast growth factor signaling and MAP kinase activation, and mediates cell adhesion and guidance via interactions with latrophilin receptors. Biallelic pathogenic variants cause autosomal recessive developmental and epileptic encephalopathy with severe intellectual disability. The gene shows moderate constraint against loss-of-function variants, with primary effects on brain development and neuronal connectivity.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the fibronectin leucine rich transmembrane protein (FLRT) family. The family members may function in cell adhesion and/or receptor signalling. Their protein structures resemble small leucine-rich proteoglycans found in the extracellular matrix. The encoded protein shares sequence similarity with two other family members, FLRT2 and FLRT3. This gene is expressed in kidney and brain. [provided by RefSeq, Jul 2008]

OMIM 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

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.59

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.59LOEUF

pLI 0.357

Z-score 2.60

OE 0.23 (0.10–0.59)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.55Z-score

OE missense 0.80 (0.73–0.87)

372 obs / 466.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.23 (0.10–0.59)

0≤0.351.4

Missense OE?0.80 (0.73–0.87)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 3 / 13.2Missense obs/exp: 372 / 466.1Syn Z: 0.53

Background carrier burden — how many people carry a rare variant somewhere in FLRT1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 58

795 rare PASS variants

Rare truncating (LoF)

1 in 5,900

43 rare PASS variants

Rare synonymous (reference)

1 in 76

392 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FLRT1. 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 74	1 in 5,100
South Asian	~43k	1 in 65	1 in 3,800
Remaining (unassigned)	~30k	1 in 57	≈ 1 in 7,500
European (Finnish)	~27k	1 in 180	≈ 1 in 12,000
Admixed American	~22k	1 in 64	≈ 1 in 5,600
African / African American	~21k	1 in 62	≈ 1 in 9,300
East Asian	~20k	1 in 40	≈ 1 in 9,900
Ashkenazi Jewish	~13k	1 in 130	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 47	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 1 coding exons well covered in gnomAD exomes and genomes.? see exons ↓