SHARPIN

Chr 8AR

SHANK associated RH domain interactor

Also known as: AIFID, SIPL1

NCBI Gene: 81858 ENSG00000179526 UniProt: Q9H0F6 OMIM: 611885

The SHARPIN protein is a component of the LUBAC complex that conjugates linear polyubiquitin chains to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation. Mutations cause autoinflammation with episodic fever and immune dysregulation through autosomal recessive inheritance. This condition affects the immune system and involves recurrent inflammatory episodes.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Enables polyubiquitin modification-dependent protein binding activity. Involved in defense response to bacterium; protein linear polyubiquitination; and regulation of signal transduction. Located in cytosol. Part of LUBAC complex. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

GOFmechanismARLOEUF 0.981 OMIM phenotype

Clinical Summary— SHARPIN

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 66 VUS of 104 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.98LOEUF

pLI 0.000

Z-score 1.63

OE 0.58 (0.35–0.98)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.04Z-score

OE missense 1.01 (0.90–1.13)

215 obs / 213.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.58 (0.35–0.98)

0≤0.351.4

Missense OE?1.01 (0.90–1.13)

0≤0.61.4

Synonymous OE?1.25

0≤1.21.6

LoF obs/exp: 10 / 17.3Missense obs/exp: 215 / 213.2Syn Z: -1.92

This gene — mechanism propensity

0.5674th %ile

GOF

0.6345th %ile

LOF

0.3259th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

104 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

VUS66

Likely Benign7

Benign6

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	0	0	0	3
Likely Pathogenic	0	0	0	0	0
VUS	0	66	0	0	66
Likely Benign	0	6	0	1	7
Benign	0	2	2	2	6
Total	3	74	2	3	82

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

61 pathogenic / likely-pathogenic (of 72) ClinVar copy-number / structural variants overlap SHARPIN — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →