CX3CL1

Chr 16

C-X3-C motif chemokine ligand 1

Also known as: ABCD-3, C3Xkine, CXC3, CXC3C, NTN, NTT, SCYD1, fractalkine

NCBI Gene: 6376 ENSG00000006210 UniProt: P78423 OMIM: 601880

The CX3CL1 protein is a chemokine that regulates immune cell adhesion, migration, and inflammatory responses by binding to the CX3CR1 receptor and various integrins. Mutations cause autosomal dominant susceptibility to severe viral infections due to impaired natural killer cell and T cell function, with patients typically presenting with life-threatening complications from common viral pathogens in childhood. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.545), reflecting its important role in antiviral immunity.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

This gene belongs to the CX3C subgroup of chemokines, characterized by the number of amino acids located between the conserved cysteine residues. This is the only member of the CX3C subgroup, which contains three amino acids between cysteine residues, resulting in a Cys-X-X-X-Cys configuration. The encoded protein contains an extended mucin-like stalk with a chemokine domain on top, and exists in both a membrane-anchored form where it acts as a binding molecule, or, in soluble form, as a chemotactic cytokine. The mature form of this protein can be cleaved at the cell surface, yielding different soluble forms that can interact with the G-protein coupled receptor, C-X3-C motif chemokine receptor 1 gene product. This gene plays a role in a wide range of diseases, including cancer, vasculitis, neuropathies, atherosclerosis, inflammatory diseases, and in human immunodeficiency virus infections. [provided by RefSeq, Sep 2017]

GeneReviews 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

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.55

LOEUF

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Mechanism

📖

GeneReview available — CX3CL1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.55LOEUF

pLI 0.608

Z-score 2.61

OE 0.17 (0.07–0.55)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.84Z-score

OE missense 0.85 (0.76–0.95)

211 obs / 248.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.17 (0.07–0.55)

0≤0.351.4

Missense OE?0.85 (0.76–0.95)

0≤0.61.4

Synonymous OE?1.23

0≤1.21.6

LoF obs/exp: 2 / 11.6Missense obs/exp: 211 / 248.4Syn Z: -1.95

Background carrier burden — how many people carry a rare variant somewhere in CX3CL1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 93

551 rare PASS variants

Rare truncating (LoF)

1 in 3,800

41 rare PASS variants

Rare synonymous (reference)

1 in 140

250 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CX3CL1. 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 120	1 in 3,700
South Asian	~43k	1 in 100	1 in 7,100
Remaining (unassigned)	~30k	1 in 72	≈ 1 in 30,000
European (Finnish)	~27k	1 in 620	1 in 2,300
Admixed American	~22k	1 in 83	1 in 1,600
African / African American	~21k	1 in 76	≈ 1 in 4,300
East Asian	~20k	1 in 120	≈ 1 in 6,500
Ashkenazi Jewish	~13k	1 in 430	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 76	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 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓