NKIRAS1

Chr 3

NFKB inhibitor interacting Ras like 1

Also known as: KBRAS1, kappaB-Ras1

NCBI Gene: 28512ENSG00000197885UniProt: Q9NYS0OMIM: 604496

The NKIRAS1 protein regulates NF-kappa-B signaling by preventing degradation of NF-kappa-B inhibitor beta and promoting cytoplasmic retention of the p65/RELA subunit. Mutations cause neurodevelopmental disorders with intellectual disability, and the gene follows autosomal recessive inheritance. The protein appears to be loss-of-function tolerant based on constraint metrics.

OMIMResearchSummary from RefSeq, UniProt
MultiplemechanismLOEUF 1.36
Clinical Summary— NKIRAS1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
32 unique Pathogenic / Likely Pathogenic· 103 VUS of 246 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
1.36LOEUF
pLI 0.001
Z-score 0.83
OE 0.69 (0.38–1.36)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
0.88Z-score
OE missense 0.75 (0.62–0.91)
74 obs / 98.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.69 (0.38–1.36)
0≤0.351.4
Missense OE0.75 (0.62–0.91)
0≤0.61.4
Synonymous OE0.97
0≤1.21.6
LoF obs/exp: 6 / 8.6Missense obs/exp: 74 / 98.5Syn Z: 0.13
DN
0.79top 25%
GOF
0.77top 25%
LOF
0.2777th %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

246 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30
Likely Pathogenic2
VUS103
Likely Benign68
Benign18
Conflicting4
30
Pathogenic
2
Likely Pathogenic
103
VUS
68
Likely Benign
18
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
2
20
0
30
Likely Pathogenic
1
1
0
0
2
VUS
2
95
3
3
103
Likely Benign
0
2
19
47
68
Benign
0
1
12
5
18
Conflicting
—4
Total111015455225

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

View in ClinVar →

Protein Context — Lollipop Plot

NKIRAS1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 4 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients