IL12A

Chr 3

interleukin 12A

Also known as: CLMF, IL-12A, NFSK, NKSF1, P35

NCBI Gene: 3592 ENSG00000168811 UniProt: P29459

This gene encodes a subunit of a cytokine that acts on T and natural killer cells, and has a broad array of biological activities. The cytokine is a disulfide-linked heterodimer composed of the 35-kD subunit encoded by this gene, and a 40-kD subunit that is a member of the cytokine receptor family. This cytokine is required for the T-cell-independent induction of interferon (IFN)-gamma, and is important for the differentiation of both Th1 and Th2 cells. The responses of lymphocytes to this cytokine are mediated by the activator of transcription protein STAT4. Nitric oxide synthase 2A (NOS2A/NOS2) is found to be required for the signaling process of this cytokine in innate immunity. [provided by RefSeq, Jul 2008]

Research

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.81

Clinical Summary— IL12A

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Population Constraint (gnomAD)

Low constraint (pLI 0.05) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

22 VUS of 28 total submissions

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

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

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.81LOEUF

pLI 0.047

Z-score 2.00

OE 0.36 (0.17–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.83Z-score

OE missense 0.80 (0.68–0.94)

108 obs / 135.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.36 (0.17–0.81)

0≤0.351.4

Missense OE?0.80 (0.68–0.94)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 4 / 11.2Missense obs/exp: 108 / 135.2Syn Z: 0.08

This gene — mechanism propensity

0.7229th %ile

GOF

0.6540th %ile

LOF

0.2092th %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

28 submitted variants in ClinVar

ClinVar

Classification Summary

VUS22

Likely Benign4

Benign2

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	22	0	22
Likely Benign	2	2	4
Benign	1	1	2
Total	25	3	28

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap IL12A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →