ISG15

Chr 1AR

ISG15 ubiquitin like modifier

Also known as: G1P2, IFI15, IMD38, IP17, UCRP, hUCRP

NCBI Gene: 9636 ENSG00000187608 UniProt: P05161 OMIM: 147571

The encoded protein is a ubiquitin-like modifier that conjugates to target proteins (ISGylation) and functions as a secreted cytokine, both critical for antiviral immunity and interferon signaling. Mutations cause immunodeficiency 38, an autosomal recessive primary immunodeficiency characterized by increased susceptibility to viral infections and mycobacterial disease. The gene shows moderate tolerance to loss-of-function variants (LOEUF 1.691), consistent with the recessive inheritance pattern where biallelic mutations are required for disease.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a ubiquitin-like protein that is conjugated to intracellular target proteins upon activation by interferon-alpha and interferon-beta. Several functions have been ascribed to the encoded protein, including chemotactic activity towards neutrophils, direction of ligated target proteins to intermediate filaments, cell-to-cell signaling, and antiviral activity during viral infections. While conjugates of this protein have been found to be noncovalently attached to intermediate filaments, this protein is sometimes secreted. [provided by RefSeq, Dec 2012]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Immunodeficiency 38MIM #616126

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Immunodeficiency 38; no ClinGen or GenCC tier

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

520

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.69

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.69LOEUF

pLI 0.405

Z-score 0.97

OE 0.00 (0.00–1.69)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.04Z-score

OE missense 1.01 (0.87–1.18)

117 obs / 115.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.00 (0.00–1.69)

0≤0.351.4

Missense OE?1.01 (0.87–1.18)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 0 / 1.1Missense obs/exp: 117 / 115.7Syn Z: -0.50

Background carrier burden — how many people carry a rare variant somewhere in ISG15?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 170

236 rare PASS variants

Rare truncating (LoF)

1 in 3,900

42 rare PASS variants

Rare synonymous (reference)

1 in 260

124 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ISG15. 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 270	1 in 3,900
South Asian	~43k	1 in 310	1 in 4,800
Remaining (unassigned)	~30k	1 in 150	≈ 1 in 10,000
European (Finnish)	~26k	1 in 510	≈ 1 in 6,600
Admixed American	~22k	1 in 110	1 in 1,900
African / African American	~21k	1 in 100	≈ 1 in 6,000
East Asian	~20k	1 in 250	1 in 2,800
Ashkenazi Jewish	~13k	1 in 1,000	none seen
Middle Eastern	~2,884	1 in 170	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 2 coding exons well covered in gnomAD exomes and genomes.? see exons ↓