ICA1

Chr 7

islet cell autoantigen 1

Also known as: ICA69, ICAp69

NCBI Gene: 3382 ENSG00000003147 UniProt: Q05084

This protein contains an arfaptin homology domain and localizes to the cytosol, Golgi complex, and immature secretory granules where it may function in neurotransmitter secretion. Pathogenic variants cause autosomal recessive spastic paraplegia with onset typically in childhood or adolescence, affecting primarily the motor system. The gene is highly constrained against loss-of-function variants (LOEUF 0.58), indicating that complete loss of protein function is likely not tolerated.

ResearchSummary from RefSeq, UniProt

This gene encodes a protein with an arfaptin homology domain that is found both in the cytosol and as membrane-bound form on the Golgi complex and immature secretory granules. This protein is believed to be an autoantigen in insulin-dependent diabetes mellitus and primary Sjogren's syndrome. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Feb 2013]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.58

Clinical Summary— ICA1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.35) despite low pLI — interpret in context.

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ClinVar Variants

81 VUS of 117 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.58LOEUF

pLI 0.001

Z-score 3.39

OE 0.35 (0.22–0.58)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.49Z-score

OE missense 0.91 (0.82–1.02)

236 obs / 258.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.35 (0.22–0.58)

0≤0.351.4

Missense OE?0.91 (0.82–1.02)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 11 / 31.6Missense obs/exp: 236 / 258.3Syn Z: -0.47

This gene — mechanism propensity

0.74top 25%

GOF

0.6542th %ile

LOF

0.3066th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

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

117 submitted variants in ClinVar

ClinVar

Classification Summary

VUS81

Likely Benign2

Benign4

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	81	0	0	81
Likely Benign	2	0	0	2
Benign	0	2	2	4
Total	83	2	2	87

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

View in ClinVar →

28 pathogenic / likely-pathogenic (of 41) ClinVar copy-number / structural variants overlap ICA1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →