CST6

Chr 11

cystatin E/M

Also known as: ECTD15

NCBI Gene: 1474 ENSG00000175315 UniProt: P04080

CST6 encodes cystatin M, an intracellular cysteine protease inhibitor that tightly binds and reversibly inhibits cathepsins L, H, and B. Mutations cause ectodermal dysplasia 15, hypohidrotic/hair type, with autosomal recessive inheritance. The gene has low constraint scores (pLI 0.37, LOEUF 0.995), indicating tolerance to loss-of-function variants in the general population.

ResearchSummary from RefSeq, OMIM, UniProt

The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins and the kininogens. The type 2 cystatin proteins are a class of cysteine proteinase inhibitors found in a variety of human fluids and secretions, where they appear to provide protective functions. This gene encodes a cystatin from the type 2 family, which is down-regulated in metastatic breast tumor cells as compared to primary tumor cells. Loss of expression is likely associated with the progression of a primary tumor to a metastatic phenotype. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtEpilepsy, progressive myoclonic 1

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

0.99

LOEUF

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

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.99LOEUF

pLI 0.372

Z-score 1.59

OE 0.21 (0.07–0.99)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.25Z-score

OE missense 0.63 (0.51–0.79)

58 obs / 91.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.21 (0.07–0.99)

0≤0.351.4

Missense OE?0.63 (0.51–0.79)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 1 / 4.7Missense obs/exp: 58 / 91.7Syn Z: -0.09

Background carrier burden — how many people carry a rare variant somewhere in CST6?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 210

219 rare PASS variants

Rare truncating (LoF)

1 in 7,300

34 rare PASS variants

Rare synonymous (reference)

1 in 630

109 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CST6. 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 260	1 in 5,500
South Asian	~43k	1 in 390	1 in 2,300
Remaining (unassigned)	~30k	1 in 350	≈ 1 in 30,000
European (Finnish)	~27k	1 in 610	≈ 1 in 10,000
Admixed American	~22k	1 in 340	≈ 1 in 11,000
African / African American	~21k	1 in 290	≈ 1 in 17,000
East Asian	~20k	1 in 270	≈ 1 in 18,000
Ashkenazi Jewish	~13k	1 in 1,600	≈ 1 in 12,000
Middle Eastern	~2,884	1 in 360	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 ↓