RAB5IF

Chr 20AR

RAB5 interacting factor

Also known as: C20orf24, CFSMR2, OPTI, PNAS-11, RCAF1, RIP5

NCBI Gene: 55969 ENSG00000101084 UniProt: Q9BUV8 OMIM: 619960

The protein is a component of the multi-pass translocon complex that mediates insertion of multi-pass membrane proteins into the ER membrane and acts as an assembly factor for mitochondrial respiratory complexes. Autosomal recessive mutations cause craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome 2. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.602), and the condition involves craniofacial, skeletal, and neurodevelopmental systems.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Involved in mitochondrial respirasome assembly and multi-pass transmembrane protein insertion into ER membrane. Located in mitochondrion. Part of multi-pass translocon complex. Implicated in craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome 2. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.601 OMIM phenotype

Clinical Summary— RAB5IF

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.67) — some intolerance to loss-of-function variants.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 3 VUS of 5 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.60LOEUF

pLI 0.670

Z-score 2.27

OE 0.13 (0.04–0.60)

Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?

0.51Z-score

OE missense 0.83 (0.67–1.03)

60 obs / 72.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.13 (0.04–0.60)

0≤0.351.4

Missense OE?0.83 (0.67–1.03)

0≤0.61.4

Synonymous OE?1.41

0≤1.21.6

LoF obs/exp: 1 / 7.9Missense obs/exp: 60 / 72.2Syn Z: -1.72

This gene — mechanism propensity

0.6453th %ile

GOF

0.74top 25%

LOF

0.2968th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction 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

5 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS3

Likely Pathogenic

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Total
Pathogenic	0	0	0
Likely Pathogenic	1	0	1
VUS	0	3	3
Likely Benign	0	0	0
Benign	0	0	0
Total	1	3	4

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 10) ClinVar copy-number / structural variants overlap RAB5IF — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →