rs2153535 — BLOC1S5

Regulatory variant near MUTED/BLOC1S5, a gene whose mouse homolog controls otolith synthesis in the vestibular labyrinth; the G allele increases susceptibility to motion sickness at genome-wide significance

See your personal result for BLOC1S5

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

MUTED/BLOC1S5 — Inner Ear Otolith Biology and Motion Sickness Susceptibility

Motion sickness is not a matter of imagination or willpower — it has a measurable genetic architecture. The largest GWAS of motion sickness to date (80,494 individuals from 23andMe) identified 35 genome-wide significant loci, and the variant near MUTED on chromosome 6 stands out for pointing directly to the sensory mechanism that makes motion perception possible in the first place: otoliths11 otoliths
calcium carbonate crystals embedded in a gel matrix within the utricle and saccule of the inner ear; they shift under gravity and linear acceleration, bending hair cells to signal head movement to the brain.

MUTED (also called BLOC1S5) encodes a subunit of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). In mice, the homolog of MUTED specifically controls the synthesis of otoliths in the vestibular labyrinth — and mice with muted mutations develop deficient otoconia, the calcium carbonate crystals that constitute the otolith mass, with proportionally impaired gravity receptor responses.

rs2153535 is a regulatory variant approximately 300 kilobases downstream of BLOC1S5 on chromosome 6p24.3. The G allele reaches genome-wide significance for motion sickness susceptibility at p = 2.7×10⁻¹⁸, with a per-allele beta of 0.046. The G allele is common globally (approximately 40%) but shows notable variation across ancestries: nearly 50% in Europeans, only 22% in East Asians.

The Mechanism

The BLOC-1 complex regulates trafficking of membrane proteins to lysosome-related organelles — in the inner ear, this includes the vesicular machinery needed to deposit calcium carbonate onto the otolith membrane during development and maintenance. Impaired BLOC1S5 function in mouse models results in reduced or abnormal otoconia, meaning the gravity-sensing mass in the utricle and saccule is diminished.

The consequence is not deafness — the auditory cochlea is unaffected by these mutations — but a selective impairment of the otolith organs' ability to transduce gravity and linear acceleration signals faithfully. When the vestibular signal is weak or asymmetric, the brain receives ambiguous information about head position and movement. Physiological studies confirm this22 Physiological studies confirm this
Singh et al. 2014 demonstrated elevated vestibular evoked myogenic potential thresholds and higher inter-aural asymmetry ratios in motion sickness-susceptible individuals compared with controls: reduced or asymmetric otolith function is the likely mechanism linking genetic vestibular variants to motion sickness susceptibility.

Motion sickness itself arises from sensory conflict — the brain receives inconsistent signals from the vestibular system, visual system, and proprioception about what motion is occurring. A vestibular system with reduced otolith fidelity generates a noisier signal, increasing the probability of that conflict threshold being crossed during passive movement (car, boat, plane, VR).

The Evidence

Hromatka et al. 201533 Hromatka et al. 2015
Genetic variants associated with motion sickness point to roles for inner ear development, neurological processes and glucose homeostasis. Human Molecular Genetics is the founding study: 80,494 participants from 23andMe, 35 genome-wide significant loci, P = 2.7×10⁻¹⁸ at rs2153535. The propensity score built from all 35 SNPs explained 2.9% of variance in motion sickness; individuals in the top 5% had 6.37-fold increased odds of frequent motion sickness. Sex-specific effects were substantial — effects up to three times stronger in women — consistent with known clinical observations that women are more frequently and severely affected by motion sickness.

The genetic overlap between motion sickness and vertigo is supported by Skuladottir et al. 202144 Skuladottir et al. 2021
A genome-wide meta-analysis uncovers six sequence variants conferring risk of vertigo. Communications Biology (48,072 vertigo cases, 894,541 controls), which found that eight motion sickness variants from Hromatka 2015 also associated with vertigo — suggesting shared vestibular pathway architecture underlies both conditions.

The causal biological link between MUTED gene function and inner ear gravity sensing is supported by Jones et al. 200455 Jones et al. 2004
Gravity receptor function in mice with graded otoconial deficiencies. Hearing Research: otoconial-deficient mice including the muted strain showed graded vestibular response impairment proportional to their degree of otolith loss.

Practical Actions

Motion sickness susceptibility from this locus is a property of the vestibular system's baseline signal fidelity, not something modifiable by supplements. The actionable strategies are behavioral and pharmacological: positioning to minimize sensory conflict (front-seat travel, horizon-facing orientation), scopolamine patches before anticipated exposure, and vestibular habituation training (a structured exposure protocol used in aerospace medicine to increase motion sickness threshold). There is emerging evidence that these training protocols produce lasting neuroadaptation even in genetically susceptible individuals.

Interactions

The MUTED locus is one of 35 genome-wide significant motion sickness loci from Hromatka 2015. Other major loci include rs66800491 near PVRL3 (eye development, strongest hit at p = 4.2×10⁻⁴⁴) and rs1195218 near AUTS2 (autism spectrum/neurodevelopment, p = 4.5×10⁻²²). The combination of multiple motion sickness risk alleles compounds susceptibility — the polygenic score across all 35 loci explains 6.37-fold odds in the top 5% versus the bottom 5%. The MUTED locus does not interact with specific drugs through pharmacogenomic mechanisms, but G allele homozygotes who respond poorly to scopolamine are likely best served by vestibular habituation training as an alternative prevention strategy.

The overlap between motion sickness and migraine susceptibility (Hromatka 2015 confirmed the genetic correlation) suggests that vestibular migraine — where migraine attacks trigger vestibular symptoms — may be especially relevant for carriers of both MUTED-region risk alleles and known migraine susceptibility variants.

Drug Interactions

scopolamine reduced_efficacy literature

Genotype Interpretations

What each possible genotype means for this variant.

CC Low Vestibular Risk Normal

Common genotype — typical vestibular otolith function, lower motion sickness susceptibility

You carry two copies of the C allele at rs2153535, the reference genotype near the MUTED/BLOC1S5 gene on chromosome 6. This is the most common genotype globally (approximately 36% of people). The C allele is associated with typical vestibular otolith function and is not linked to elevated motion sickness susceptibility in the Hromatka 2015 GWAS of 80,494 individuals. Your risk from this locus is at the population baseline.

CG One Risk Allele Intermediate

One G allele — moderately increased motion sickness susceptibility via vestibular mechanism

The MUTED gene (BLOC1S5) encodes a subunit of the BLOC-1 complex, which regulates trafficking of proteins to lysosome-related organelles. In the inner ear, this includes the machinery required for normal otolith synthesis — the calcium carbonate crystals in the utricle and saccule that transduce gravity and linear acceleration into neural signals. The rs2153535 variant is a regulatory SNP located approximately 300 kb downstream of BLOC1S5, and likely modulates its expression or the expression of nearby genes involved in this pathway.

Carriers of one G allele experience an intermediate effect: slightly noisier or asymmetric vestibular input that makes the sensory conflict threshold easier to trigger during car travel, boat journeys, flights, or virtual reality exposure. Women with this genotype may experience stronger effects — the Hromatka 2015 study found sex-specific effects up to 3× stronger in women, consistent with known clinical observations.

GG Two Risk Alleles High Risk

Two G alleles — highest motion sickness susceptibility at this locus, mediated by vestibular otolith biology

MUTED (BLOC1S5) is named for its role in mouse coat colour (the muted mutation produces a diluted coat pigment), but its clinically relevant function in humans is in lysosomal organelle biogenesis, specifically in the inner ear vestibular system. The BLOC-1 complex that MUTED/BLOC1S5 contributes to controls intracellular vesicle trafficking; in the inner ear hair cell epithelia, this trafficking is required for the synthesis and maintenance of otoconia — the calcium carbonate crystals embedded in the otolith gel matrix of the utricle and saccule.

When otolith mass or quality is reduced, the hair cell mechanosensors receive a weaker or noisier linear acceleration signal. Physiological evidence supports this pathway: motion sickness-susceptible individuals have higher vestibular evoked myogenic potential thresholds and greater inter-aural asymmetry than controls (Singh et al. 2014), consistent with impaired otolith transduction as a predisposing factor.

At the GG genotype you are carrying the maximum allele dose from this locus. Depending on your genotype at the other 34 motion sickness loci identified in Hromatka 2015, your overall polygenic susceptibility may be substantially elevated — individuals in the top 5% of the polygenic distribution had 6.37-fold increased odds of frequent motion sickness compared with those in the bottom 5%.

Vestibular habituation training — a structured, progressive exposure protocol used in aerospace medicine — is the most durable long-term strategy. Studies show it produces lasting neuroadaptation even in genetically susceptible individuals.