RIN2

Chr 20AR

Ras and Rab interactor 2

Also known as: MACS, RASSF4

NCBI Gene: 54453ENSG00000132669UniProt: Q8WYP3OMIM: 610222

The protein functions as a guanine nucleotide exchange factor for RAB5, regulating membrane trafficking in the early endocytic pathway. Biallelic mutations cause macrocephaly, alopecia, cutis laxa, and scoliosis (MACS) syndrome, a connective tissue disorder affecting elastic tissues with autosomal recessive inheritance. The gene shows low constraint to loss-of-function variation (pLI 0.0008, LOEUF 0.549), consistent with the recessive inheritance pattern.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismARLOEUF 0.551 OMIM phenotype
Clinical Summary— RIN2
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Gene-Disease Validity (ClinGen)
RIN2 syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.
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ClinVar Variants
14 unique Pathogenic / Likely Pathogenic· 223 VUS of 400 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
0.55LOEUF
pLI 0.001
Z-score 3.65
OE 0.34 (0.22–0.55)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
0.72Z-score
OE missense 0.91 (0.85–0.98)
490 obs / 537.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.34 (0.22–0.55)
0≤0.351.4
Missense OE0.91 (0.85–0.98)
0≤0.61.4
Synonymous OE0.97
0≤1.21.6
LoF obs/exp: 12 / 35.4Missense obs/exp: 490 / 537.2Syn Z: 0.36
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongRIN2-related macrocephaly, alopecia, cutis laxa, and scoliosis tall forehead, sparse hair, skin hyperextensibility, and scoliosisLOFAR

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

DN
0.6646th %ile
GOF
0.6052th %ile
LOF
0.3454th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

400 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11
Likely Pathogenic3
VUS223
Likely Benign138
Benign3
Conflicting3
11
Pathogenic
3
Likely Pathogenic
223
VUS
138
Likely Benign
3
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
0
5
0
11
Likely Pathogenic
2
0
1
0
3
VUS
6
204
8
5
223
Likely Benign
0
1
44
93
138
Benign
0
1
0
2
3
Conflicting
—3
Total1420658100381

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

View in ClinVar →

Protein Context — Lollipop Plot

RIN2 · 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.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
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