RIMKLA

Chr 1

ribosomal modification protein rimK like family member A

Also known as: FAM80A, NAAGS, NAAGS-II, NAAGS2

NCBI Gene: 284716 ENSG00000177181 UniProt: Q8IXN7 OMIM: 618949

This enzyme catalyzes the synthesis of N-acetyl-L-aspartyl-L-glutamate (NAAG) and related compounds in the cytoplasm. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by seizures, developmental delays, and progressive neurological deterioration. The gene shows minimal constraint against loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable N-acetyl-L-aspartate-L-glutamate ligase activity. Predicted to be involved in glutamine family amino acid metabolic process. Predicted to be located in cytosol. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.01

Clinical Summary— RIMKLA

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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

35 VUS of 41 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?

1.01LOEUF

pLI 0.001

Z-score 1.53

OE 0.54 (0.31–1.01)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.22Z-score

OE missense 0.76 (0.67–0.87)

160 obs / 209.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.54 (0.31–1.01)

0≤0.351.4

Missense OE?0.76 (0.67–0.87)

0≤0.61.4

Synonymous OE?0.77

0≤1.21.6

LoF obs/exp: 7 / 12.9Missense obs/exp: 160 / 209.7Syn Z: 1.63

This gene — mechanism propensity

0.6842th %ile

GOF

0.6833th %ile

LOF

0.2969th %ile

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

GOFprediction above median

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

41 submitted variants in ClinVar

ClinVar

Classification Summary

VUS35

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	35	35
Likely Benign	0	0
Benign	0	0
Total	35	35

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap RIMKLA — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →