CMTM6

Chr 3

CKLF like MARVEL transmembrane domain containing 6

Also known as: CKLFSF6, PRO2219

NCBI Gene: 54918 ENSG00000091317 UniProt: Q9NX76 OMIM: 607889

The CMTM6 protein regulates PD-L1 expression on immune cells by protecting it from degradation and maintaining its presence at the cell surface, thereby controlling immune tolerance and T-cell responses. Mutations in CMTM6 cause autosomal recessive combined immunodeficiency affecting adaptive immunity. The gene shows moderate constraint against loss-of-function variants, and patients typically present with recurrent infections and immune dysregulation in early childhood.

OMIM ResearchSummary from RefSeq, UniProt

This gene belongs to the chemokine-like factor gene superfamily, a novel family that is similar to the chemokine and transmembrane 4 superfamilies. This gene is one of several chemokine-like factor genes located in a cluster on chromosome 3. This gene is widely expressed in many tissues, but the exact function of the encoded protein is unknown. [provided by RefSeq, Jul 2008]

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

0.88

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.88LOEUF

pLI 0.433

Z-score 1.75

OE 0.19 (0.07–0.88)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.50Z-score

OE missense 0.85 (0.70–1.03)

74 obs / 87.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.19 (0.07–0.88)

0≤0.351.4

Missense OE?0.85 (0.70–1.03)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 1 / 5.4Missense obs/exp: 74 / 87.3Syn Z: -0.29

Background carrier burden — how many people carry a rare variant somewhere in CMTM6?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 490

219 rare PASS variants

Rare truncating (LoF)

1 in 5,600

29 rare PASS variants

Rare synonymous (reference)

1 in 600

104 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CMTM6. 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 780	1 in 4,900
South Asian	~43k	1 in 140	1 in 2,100
Remaining (unassigned)	~30k	1 in 430	≈ 1 in 7,500
European (Finnish)	~27k	1 in 3,400	none seen
Admixed American	~22k	1 in 230	1 in 3,100
African / African American	~21k	1 in 270	≈ 1 in 5,700
East Asian	~20k	1 in 370	≈ 1 in 7,800
Ashkenazi Jewish	~13k	1 in 370	1 in 2,200
Middle Eastern	~2,884	1 in 280	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 4 coding exons well covered in gnomAD exomes and genomes.? see exons ↓