GAREM2

Chr 2

GRB2 associated regulator of MAPK1 subtype 2

Also known as: FAM59B, GAREML

NCBI Gene: 150946 ENSG00000157833 UniProt: Q75VX8 OMIM: 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.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to act upstream of or within several processes, including cognition; neuron projection extension; and social behavior. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.49

Clinical Summary— GAREM2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.

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ClinVar Variants

130 unique Pathogenic / Likely Pathogenic· 173 VUS of 667 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?

0.49LOEUF

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 OE?0.22 (0.10–0.49)

0≤0.351.4

Missense OE?0.74 (0.67–0.82)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 4 / 18.5Missense obs/exp: 264 / 355.8Syn Z: 0.77

This gene — mechanism propensity

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.

LOF91% 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

667 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic48

Likely Pathogenic82

VUS173

Likely Benign289

Benign33

Conflicting21

Pathogenic

Likely Pathogenic

173

VUS

289

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	47	0	1	0	48
Likely Pathogenic	71	10	1	0	82
VUS	4	141	21	7	173
Likely Benign	0	4	122	163	289
Benign	0	2	31	0	33
Conflicting	—				21
Total	122	157	176	170	646

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 24) ClinVar copy-number / structural variants overlap GAREM2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →