CXCL12

Chr 10

C-X-C motif chemokine ligand 12

Also known as: IRH, PBSF, SCYB12, SDF1, TLSF, TPAR1

NCBI Gene: 6387 ENSG00000107562 UniProt: P48061 OMIM: 600835

The encoded protein is a chemokine that functions as a chemoattractant for T-lymphocytes and monocytes, activating the CXCR4 receptor to induce calcium mobilization and cell migration, and playing critical roles in immune cell trafficking, embryonic development, and B-cell lymphopoiesis. Mutations in this gene are associated with resistance to HIV-1 infection. The gene shows relatively low constraint to loss-of-function variation (pLI 0.12, LOEUF 1.18), suggesting tolerance to protein-truncating variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This antimicrobial gene encodes a stromal cell-derived alpha chemokine member of the intercrine family. The encoded protein functions as the ligand for the G-protein coupled receptor, chemokine (C-X-C motif) receptor 4, and plays a role in many diverse cellular functions, including embryogenesis, immune surveillance, inflammation response, tissue homeostasis, and tumor growth and metastasis. Mutations in this gene are associated with resistance to human immunodeficiency virus type 1 infections. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2014]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

{AIDS, resistance to}MIM #609423

Active trials

915

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.18

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.18LOEUF

pLI 0.119

Z-score 1.33

OE 0.38 (0.15–1.18)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.25Z-score

OE missense 1.08 (0.91–1.29)

87 obs / 80.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.38 (0.15–1.18)

0≤0.351.4

Missense OE?1.08 (0.91–1.29)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 2 / 5.3Missense obs/exp: 87 / 80.6Syn Z: 0.16

Background carrier burden — how many people carry a rare variant somewhere in CXCL12?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

344 rare PASS variants

Rare truncating (LoF)

1 in 2,400

53 rare PASS variants

Rare synonymous (reference)

1 in 290

123 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CXCL12. 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 170	1 in 2,500
South Asian	~43k	1 in 120	1 in 5,200
Remaining (unassigned)	~30k	1 in 120	1 in 1,800
European (Finnish)	~27k	1 in 490	≈ 1 in 27,000
Admixed American	~22k	1 in 120	1 in 2,800
African / African American	~21k	1 in 150	1 in 1,500
East Asian	~20k	1 in 150	1 in 740
Ashkenazi Jewish	~13k	1 in 1,200	none seen
Middle Eastern	~2,884	1 in 110	≈ 1 in 2,800

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): 2 of 3 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: 2 of 3 (exon 1 below).? see exons ↓