RIN2

Chr 20

Ras and Rab interactor 2

Also known as: MACS, RASSF4

NCBI Gene: 54453 ENSG00000132669 UniProt: Q8WYP3

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.

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.55

Clinical Summary— RIN2

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Gene-Disease Validity (ClinGen)

RIN2 syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

18 unique Pathogenic / Likely Pathogenic· 316 VUS of 700 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.34 (0.22–0.55)

0≤0.351.4

Missense OE?0.91 (0.85–0.98)

0≤0.61.4

Synonymous OE?0.97

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

This gene — mechanism propensity

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

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

700 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12

Likely Pathogenic6

VUS316

Likely Benign285

Benign44

Conflicting18

Pathogenic

Likely Pathogenic

316

VUS

285

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	12	0	0	0	12
Likely Pathogenic	6	0	0	0	6
VUS	11	293	7	5	316
Likely Benign	0	10	97	178	285
Benign	1	9	26	8	44
Conflicting	—				18
Total	30	312	130	191	681

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

View in ClinVar →

24 pathogenic / likely-pathogenic (of 28) ClinVar copy-number / structural variants overlap RIN2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →