CYRIB

Chr 8

CYFIP related Rac1 interactor B

Also known as: BM-009, CYRI, CYRI-B, FAM49B, L1

NCBI Gene: 51571 ENSG00000153310 UniProt: Q9NUQ9 OMIM: 617978

The CYRIB protein negatively regulates RAC1 signaling and controls cytoskeletal remodeling, cell migration, and mitochondrial dynamics while also protecting against bacterial infections. Mutations cause autosomal dominant developmental and epileptic encephalopathy with microcephaly, affecting the brain and resulting in seizures and developmental delays typically beginning in infancy. The gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to be pathogenic.

OMIM ResearchSummary from RefSeq, UniProt

Enables small GTPase binding activity. Involved in several processes, including cellular response to molecule of bacterial origin; negative regulation of small GTPase mediated signal transduction; and regulation of organelle organization. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.31

Clinical Summary— CYRIB

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

12 VUS of 31 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.31LOEUF

pLI 0.976

Z-score 3.76

OE 0.10 (0.04–0.31)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.21Z-score

OE missense 0.30 (0.24–0.38)

51 obs / 168.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.10 (0.04–0.31)

0≤0.351.4

Missense OE?0.30 (0.24–0.38)

0≤0.61.4

Synonymous OE?0.73

0≤1.21.6

LoF obs/exp: 2 / 20.3Missense obs/exp: 51 / 168.2Syn Z: 1.60

This gene — mechanism propensity

0.5477th %ile

GOF

0.71top 25%

LOF

0.51top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.31

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

31 submitted variants in ClinVar

ClinVar

Classification Summary

VUS12

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	12	12
Likely Benign	0	0
Benign	0	0
Total	12	12

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

View in ClinVar →

54 pathogenic / likely-pathogenic (of 65) ClinVar copy-number / structural variants overlap CYRIB — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →