LRFN4

Chr 11

leucine rich repeat and fibronectin type III domain containing 4

Also known as: FIGLER6, SALM3, SALM3.

NCBI Gene: 78999 ENSG00000173621 UniProt: Q6PJG9 OMIM: 612810

The LRFN4 protein promotes neurite outgrowth in hippocampal neurons and is involved in synaptic membrane adhesion and regulation of presynaptic and postsynaptic density assembly. Mutations cause autosomal recessive neurodevelopmental disorder with developmental delay, intellectual disability, and autistic features. This gene is highly constrained against loss-of-function variants (pLI = 0.91, LOEUF = 0.387), suggesting that complete loss of protein function is poorly tolerated.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to be involved in regulation of postsynaptic density assembly; regulation of presynapse assembly; and synaptic membrane adhesion. Predicted to be located in plasma membrane. Predicted to be active in cell surface; glutamatergic synapse; and postsynaptic density membrane. [provided by Alliance of Genome Resources, Jun 2026]

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

0.39

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.39LOEUF

pLI 0.913

Z-score 2.98

OE 0.08 (0.03–0.39)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.25Z-score

OE missense 0.83 (0.76–0.91)

347 obs / 419.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.08 (0.03–0.39)

0≤0.351.4

Missense OE?0.83 (0.76–0.91)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 1 / 12.2Missense obs/exp: 347 / 419.1Syn Z: -0.93

Background carrier burden — how many people carry a rare variant somewhere in LRFN4?

gnomAD v4 · ~730k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 61

962 rare PASS variants

Rare truncating (LoF)

1 in 1,800

94 rare PASS variants

Rare synonymous (reference)

1 in 59

545 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for LRFN4. 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 79	1 in 2,600
South Asian	~43k	1 in 41	1 in 3,300
Remaining (unassigned)	~30k	1 in 54	1 in 5,400
European (Finnish)	~26k	1 in 150	1 in 980
Admixed American	~22k	1 in 64	1 in 1,900
African / African American	~21k	1 in 55	1 in 1,100
East Asian	~20k	1 in 65	1 in 1,100
Ashkenazi Jewish	~13k	1 in 260	1 in 1,000
Middle Eastern	~2,884	1 in 55	≈ 1 in 2,900

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 2 coding exons well covered in gnomAD exomes and genomes.? see exons ↓