GAREM2

Chr 2

GRB2 associated regulator of MAPK1 subtype 2

Also known as: FAM59B, GAREML

NCBI Gene: 150946ENSG00000157833UniProt: Q75VX8OMIM: 617999

The protein functions as an adapter that links epidermal growth factor receptor to the MAPK/ERK signaling pathway and is predicted to regulate cognition, neuron projection extension, and social behavior. Mutations cause autosomal recessive neurodevelopmental disorders with intellectual disability and behavioral abnormalities. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.49), suggesting intolerance to complete protein loss.

OMIMResearchSummary from RefSeq, UniProt
MultiplemechanismLOEUF 0.49
Clinical Summary— GAREM2
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.
📋
ClinVar Variants
112 unique Pathogenic / Likely Pathogenic· 132 VUS of 490 total submissions
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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.49LOEUF
pLI 0.439
Z-score 3.13
OE 0.22 (0.10–0.49)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
1.73Z-score
OE missense 0.74 (0.67–0.82)
264 obs / 355.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.22 (0.10–0.49)
0≤0.351.4
Missense OE0.74 (0.67–0.82)
0≤0.61.4
Synonymous OE0.92
0≤1.21.6
LoF obs/exp: 4 / 18.5Missense obs/exp: 264 / 355.8Syn Z: 0.77
DN
0.5870th %ile
GOF
0.72top 25%
LOF
0.4627th %ile

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.

LOF82% of P/LP variants are LoF · LOEUF 0.49
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

490 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic48
Likely Pathogenic64
VUS132
Likely Benign202
Benign10
Conflicting12
48
Pathogenic
64
Likely Pathogenic
132
VUS
202
Likely Benign
10
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
33
0
15
0
48
Likely Pathogenic
59
4
1
0
64
VUS
1
107
18
6
132
Likely Benign
0
2
95
105
202
Benign
0
1
9
0
10
Conflicting
—12
Total93114138111468

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

View in ClinVar →

Protein Context — Lollipop Plot

GAREM2 · 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.

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Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
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