NRROS

Chr 3AR

negative regulator of reactive oxygen species

Also known as: ELLP3030, GARPL1, LRRC33, SENEBAC, UNQ3030

NCBI Gene: 375387ENSG00000174004UniProt: Q86YC3

NRROS encodes a key regulator of TGF-beta-1 activation that is specifically required for microglia function in the nervous system, where it associates with latency-associated peptide to enable localized TGF-beta-1 signaling. Biallelic mutations cause autosomal recessive early-onset seizures with neurodegeneration and brain calcification. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.531), consistent with its essential role in microglial regulation of neuroinflammation.

Summary from RefSeq, OMIM, UniProt
Research Assistant →

Primary Disease Associations & Inheritance

Seizures, early-onset, with neurodegeneration and brain calcificationMIM #618875
AR
0
Active trials
4
Pubs (1 yr)
101
P/LP submissions
2%
P/LP missense
0.53
LOEUF
LOF
Mechanism· G2P
Clinical Summary— NRROS
🧬
Gene-Disease Validity (ClinGen)
seizures, early-onset, with neurodegeneration and brain calcifications · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.
📋
ClinVar Variants
99 unique Pathogenic / Likely Pathogenic· 111 VUS of 240 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.53LOEUF
pLI 0.326
Z-score 2.96
OE 0.23 (0.11–0.53)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
0.89Z-score
OE missense 0.88 (0.81–0.96)
379 obs / 431.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.23 (0.11–0.53)
0≤0.351.4
Missense OE0.88 (0.81–0.96)
0≤0.61.4
Synonymous OE1.05
0≤1.21.6
LoF obs/exp: 4 / 17.2Missense obs/exp: 379 / 431.1Syn Z: -0.61
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongNRROS-related infantile-onset neurodegeneration with intracranial calcificationLOFAR

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

DN
0.6065th %ile
GOF
0.6931th %ile
LOF
0.3648th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

240 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic91
Likely Pathogenic8
VUS111
Likely Benign18
Benign6
Conflicting3
91
Pathogenic
8
Likely Pathogenic
111
VUS
18
Likely Benign
6
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
2
86
0
91
Likely Pathogenic
2
0
6
0
8
VUS
0
96
15
0
111
Likely Benign
0
14
2
2
18
Benign
0
2
0
4
6
Conflicting
—3
Total51141096237

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

View in ClinVar →

Protein Context — Lollipop Plot

NRROS · protein map & ClinVar variants

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

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 4 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 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