RIN2

Chr 20AR

Ras and Rab interactor 2

Also known as: MACS, RASSF4

NCBI Gene: 54453ENSG00000132669UniProt: Q8WYP3

The RAB5 protein is a small GTPase involved in membrane trafficking in the early endocytic pathway. The protein encoded by this gene binds the GTP-bound form of the RAB5 protein preferentially over the GDP-bound form, and functions as a guanine nucleotide exchange factor for RAB5. The encoded protein is found primarily as a tetramer in the cytoplasm and does not bind other members of the RAB family. Mutations in this gene cause macrocephaly alopecia cutis laxa and scoliosis (MACS) syndrome, an elastic tissue disorder, as well as the related connective tissue disorder, RIN2 syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2011]

Primary Disease Associations & Inheritance

Macrocephaly, alopecia, cutis laxa, and scoliosisMIM #613075
AR
UniProtMACS syndrome
408
ClinVar variants
25
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— RIN2
🧬
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.
📋
ClinVar Variants
25 Pathogenic / Likely Pathogenic· 187 VUS of 408 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.72Z-score
OE missense 0.91 (0.85–0.98)
490 obs / 537.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.34 (0.22–0.55)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.85–0.98)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.97
0≤1.21.6
LoF obs/exp: 12 / 35.4Missense obs/exp: 490 / 537.2Syn Z: 0.36

ClinVar Variant Classifications

408 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20
Likely Pathogenic5
VUS187
Likely Benign159
Benign28
Conflicting9
20
Pathogenic
5
Likely Pathogenic
187
VUS
159
Likely Benign
28
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
0
14
0
20
Likely Pathogenic
3
0
2
0
5
VUS
2
175
7
3
187
Likely Benign
0
5
62
92
159
Benign
0
3
19
6
28
Conflicting
—9
Total11183104101408

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.

Gene2Phenotype Curations

RIN2-related macrocephaly, alopecia, cutis laxa, and scoliosis tall forehead, sparse hair, skin hyperextensibility, and scoliosis

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Macrocephaly, alopecia, cutis laxa, and scoliosis

MIM #613075

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
RIN2 syndrome: Expanding the clinical phenotype.
Rosato S et al.·Am J Med Genet A
2016Review
Leukoencephalopathy in RIN2 syndrome: Novel mutation and expansion of clinical spectrum.
Kameli R et al.·Eur J Med Genet
2020
Newly described clinical features in two siblings with MACS syndrome and a novel mutation in RIN2.
Aslanger AD et al.·Am J Med Genet A
2014Review
The RIN2 syndrome: a new autosomal recessive connective tissue disorder caused by deficiency of Ras and Rab interactor 2 (RIN2).
Syx D et al.·Hum Genet
2010Case report
RIN2 and BBS7 variants as cause of a coincidental syndrome.
Shaukat M et al.·Eur J Med Genet
2020Case report
RIN2 deficiency results in macrocephaly, alopecia, cutis laxa, and scoliosis: MACS syndrome.
Basel-Vanagaite L et al.·Am J Hum Genet
2009
Identification of monocyte-associated biomarkers in systemic lupus erythematosus and their pan-cancer analysis.
Chen H et al.·Lupus
2023
Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa.
Gardeitchik T et al.·Eur J Hum Genet
2014
Genetic analysis of hereditary gingival fibromatosis using whole exome sequencing and bioinformatics.
Hwang J et al.·Oral Dis
2017
Unique presentation of cutis laxa with Leigh-like syndrome due to ECHS1 deficiency.
Balasubramaniam S et al.·J Inherit Metab Dis
2017Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools