REPS2

Chr X

RALBP1 associated Eps domain containing 2

Also known as: POB1

NCBI Gene: 9185 ENSG00000169891 UniProt: Q8NFH8 OMIM: 300317

The REPS2 protein regulates endocytosis of growth factor receptors including EGF and insulin receptors, controlling receptor internalization and downstream signaling pathways that affect cell survival, adhesion, and migration. Mutations cause autosomal recessive intellectual disability with microcephaly and seizures, typically presenting in early childhood. The gene is moderately constrained against loss-of-function variants (LOEUF 0.486), suggesting some intolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, UniProt

The product of this gene is part of a protein complex that regulates the endocytosis of growth factor receptors. The encoded protein directly interacts with a GTPase activating protein that functions downstream of the small G protein Ral. Its expression can negatively affect receptor internalization and inhibit growth factor signaling. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.49

Clinical Summary— REPS2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

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ClinVar Variants

58 VUS of 162 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 0.203

Z-score 3.45

OE 0.25 (0.13–0.49)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.31Z-score

OE missense 0.76 (0.67–0.86)

174 obs / 230.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.25 (0.13–0.49)

0≤0.351.4

Missense OE?0.76 (0.67–0.86)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 6 / 24.4Missense obs/exp: 174 / 230.0Syn Z: -0.55

This gene — mechanism propensity

0.5869th %ile

GOF

0.6542th %ile

LOF

0.51top 25%

The highest-scoring mechanism for this gene is gain-of-function.

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.

ClinVar Variant Classifications

162 submitted variants in ClinVar

ClinVar

Classification Summary

VUS58

Likely Benign6

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	57	0	0	58
Likely Benign	0	3	1	2	6
Benign	0	0	0	0	0
Total	1	60	1	2	64

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

View in ClinVar →

33 pathogenic / likely-pathogenic (of 38) ClinVar copy-number / structural variants overlap REPS2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →