NLRC3

Chr 16

NLR family CARD domain containing 3

Also known as: CLR16.2, NOD3

NCBI Gene: 197358 ENSG00000167984 UniProt: Q7RTR2 OMIM: 615648

The protein encoded by this gene is a cytosolic negative regulator of innate immune responses that attenuates Toll-like receptor and STING signaling pathways and inhibits the PI3K-AKT-mTOR pathway to control cell proliferation. Mutations cause autosomal recessive autoinflammatory disease with immunodeficiency. The gene shows tolerance to loss-of-function variation (LOEUF 1.243), suggesting that complete loss of protein function may be required for disease manifestation.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a NOD-like receptor family member. The encoded protein is a cytosolic regulator of innate immunity. This protein directly interacts with stimulator of interferon genes (STING), to prevent its proper trafficking, resulting in disruption of STING-dependent activation of the innate immune response. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.24

Clinical Summary— NLRC3

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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

159 VUS of 238 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.24LOEUF

pLI 0.000

Z-score 0.29

OE 0.95 (0.74–1.24)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.49Z-score

OE missense 1.05 (0.99–1.12)

705 obs / 669.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.95 (0.74–1.24)

0≤0.351.4

Missense OE?1.05 (0.99–1.12)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 39 / 41.0Missense obs/exp: 705 / 669.1Syn Z: -1.24

This gene — mechanism propensity

0.6358th %ile

GOF

0.6052th %ile

LOF

0.3162th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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

238 submitted variants in ClinVar

ClinVar

Classification Summary

VUS159

Likely Benign20

Benign5

159

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	158	1	0	159
Likely Benign	17	0	3	20
Benign	3	1	1	5
Total	178	2	4	184

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

View in ClinVar →

37 pathogenic / likely-pathogenic (of 58) ClinVar copy-number / structural variants overlap NLRC3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →