KLRC4

Chr 12

killer cell lectin like receptor C4

Also known as: NKG2-F, NKG2F

NCBI Gene: 8302 ENSG00000183542 UniProt: O43908 OMIM: 602893

KLRC4 encodes a C-type lectin receptor expressed on natural killer (NK) cells that recognizes MHC class I HLA-E molecules and regulates NK cell-mediated immune responses. The gene shows low constraint to loss-of-function variation (pLI 0.006, LOEUF 1.46), and no Mendelian diseases have been definitively associated with KLRC4 mutations. KLRC4 variants are not established causes of pediatric neurological disorders at this time.

OMIM ResearchSummary from RefSeq, UniProt

Natural killer (NK) cells are lymphocytes that can mediate lysis of certain tumor cells and virus-infected cells without previous activation. They can also regulate specific humoral and cell-mediated immunity. NK cells preferentially express several calcium-dependent (C-type) lectins, which have been implicated in the regulation of NK cell function. This gene is a member of the NKG2 group of genes that are expressed primarily in natural killer (NK) cells. These family members encode transmembrane proteins that are characterized by a type II membrane orientation (have an extracellular C-terminus) and the presence of a C-type lectin domain. This family member is located within the NK complex, a region that contains several C-type lectin genes preferentially expressed in NK cells. Read-through transcription exists between this gene and the downstream KLRK1 (killer cell lectin-like receptor subfamily K, member 1) family member. [provided by RefSeq, Dec 2010]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.46

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.46LOEUF

pLI 0.006

Z-score 0.81

OE 0.65 (0.32–1.46)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.51Z-score

OE missense 0.84 (0.69–1.03)

66 obs / 78.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.65 (0.32–1.46)

0≤0.351.4

Missense OE?0.84 (0.69–1.03)

0≤0.61.4

Synonymous OE?1.24

0≤1.21.6

LoF obs/exp: 4 / 6.2Missense obs/exp: 66 / 78.7Syn Z: -0.98

Background carrier burden — how many people carry a rare variant somewhere in KLRC4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 460

172 rare PASS variants

Rare truncating (LoF)

1 in 3,000

35 rare PASS variants

Rare synonymous (reference)

1 in 2,000

57 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KLRC4. 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 700	1 in 5,600
South Asian	~43k	1 in 290	1 in 6,000
Remaining (unassigned)	~30k	1 in 280	1 in 5,000
European (Finnish)	~27k	1 in 890	≈ 1 in 6,700
Admixed American	~22k	1 in 490	1 in 4,400
African / African American	~21k	1 in 200	1 in 1,600
East Asian	~20k	1 in 380	≈ 1 in 6,600
Ashkenazi Jewish	~13k	1 in 1,700	none seen
Middle Eastern	~2,884	1 in 480	≈ 1 in 720

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): 3 of 4 coding exons well covered in gnomAD exomes; exon 3 marginal. Genomes: all 4.? see exons ↓