LRRC4C

Chr 11

leucine rich repeat containing 4C

Also known as: NGL-1, NGL1

NCBI Gene: 57689 ENSG00000148948 UniProt: Q9HCJ2

The LRRC4C protein (NGL1) binds specifically to netrin G1 and promotes neurite outgrowth of developing thalamic neurons. Mutations in this highly constrained gene cause neurodevelopmental disorders with autosomal recessive inheritance. The gene shows extremely high constraint against loss-of-function variants in the general population.

ResearchSummary from RefSeq, UniProt

NGL1 is a specific binding partner for netrin G1 (NTNG1; MIM 608818), which is a member of the netrin family of axon guidance molecules (Lin et al., 2003 [PubMed 14595443]).[supplied by OMIM, Mar 2008]

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

0.31

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?

0.31LOEUF

pLI 0.972

Z-score 3.41

OE 0.06 (0.02–0.31)

Highly constrained

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

Missense Constraint?

2.52Z-score

OE missense 0.63 (0.56–0.70)

224 obs / 358.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.31)

0≤0.351.4

Missense OE?0.63 (0.56–0.70)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 1 / 15.5Missense obs/exp: 224 / 358.1Syn Z: -0.30

Background carrier burden — how many people carry a rare variant somewhere in LRRC4C?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

614 rare PASS variants

Rare truncating (LoF)

1 in 19,000

13 rare PASS variants

Rare synonymous (reference)

1 in 110

355 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for LRRC4C. 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 140	1 in 22,000
South Asian	~43k	1 in 140	none seen
Remaining (unassigned)	~30k	1 in 80	≈ 1 in 10,000
European (Finnish)	~27k	1 in 290	1 in 3,800
Admixed American	~22k	1 in 87	≈ 1 in 11,000
African / African American	~21k	1 in 110	≈ 1 in 17,000
East Asian	~20k	1 in 93	none seen
Ashkenazi Jewish	~13k	1 in 350	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 180	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.