TMEM240

Chr 1AD

transmembrane protein 240

Also known as: C1orf70, SCA21

NCBI Gene: 339453ENSG00000205090UniProt: Q5SV17

This gene encodes a transmembrane-domain containing protein found in the brain and cerebellum. Mutations in this gene result in spinocerebellar ataxia 21. [provided by RefSeq, Dec 2014]

Primary Disease Associations & Inheritance

Spinocerebellar ataxia 21MIM #607454
AD
310
ClinVar variants
135
Pathogenic / LP
0.23
pLI score
1
Active trials
Clinical Summary— TMEM240
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.
📋
ClinVar Variants
135 Pathogenic / Likely Pathogenic· 97 VUS of 310 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.87LOEUF
pLI 0.229
Z-score 1.80
OE 0.28 (0.11–0.87)
Tolerant

Typical tolerance to LoF variation

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.
1.55Z-score
OE missense 0.58 (0.47–0.72)
62 obs / 107.0 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.0.28 (0.11–0.87)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.58 (0.47–0.72)
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.1.10
0≤1.21.6
LoF obs/exp: 2 / 7.2Missense obs/exp: 62 / 107.0Syn Z: -0.55

ClinVar Variant Classifications

310 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic126
Likely Pathogenic9
VUS97
Likely Benign53
Benign17
Conflicting8
126
Pathogenic
9
Likely Pathogenic
97
VUS
53
Likely Benign
17
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
126
0
126
Likely Pathogenic
0
2
7
0
9
VUS
3
67
27
0
97
Likely Benign
0
5
19
29
53
Benign
0
1
10
6
17
Conflicting
—8
Total37518935310

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

View in ClinVar →

Protein Context — Lollipop Plot

TMEM240 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

TMEM240-related spinocerebellar ataxia and intellectual disability

definitive
ADLoss 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

Spinocerebellar ataxia 21

MIM #607454

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Orphan Peripheral Neuropathies.
Finsterer J et al.·J Neuromuscul Dis
2021Review
Myoclonus and Dystonia as Recurrent Presenting Features in Patients with the SCA21-Associated TMEM240 p.Pro170Leu Variant.
Sorrentino U et al.·Tremor Other Hyperkinet Mov (N Y)
2024Review
The movement disorder spectrum of SCA21 (ATX-TMEM240): 3 novel families and systematic review of the literature.
Traschütz A et al.·Parkinsonism Relat Disord
2019Case report
The Neurodevelopmental and Motor Phenotype of SCA21 (ATX-TMEM240).
Burdekin ED et al.·J Child Neurol
2020
Developmental and Epileptic Encephalopathy as a Novel Clinical Hallmark of SCA21.
Mastrangelo M et al.·Neuropediatrics
2025Case report
Dystonic Tremor as Main Clinical Manifestation of SCA21.
Yahya V et al.·Mov Disord Clin Pract
2024
A Pyroptosis-Related Gene Signature Predicts Prognosis and Tumor Immune Microenvironment in Colorectal Cancer.
Li L et al.·Technol Cancer Res Treat
2024
Pearls & Oy-sters: SCA21 Due to TMEM240 Variation Presenting as Myoclonus Dystonia Syndrome.
Cherian A et al.·Neurology
2022Case report
A next generation sequencing-based analysis of a large cohort of ataxic patients refines the clinical spectrum associated with spinocerebellar ataxia 21.
Riso V et al.·Eur J Neurol
2021Cohort
The First Korean Family of Spinocerebellar Ataxia 21 (ATX-TMEM240) with Facial Dystonic Phenotype.
Park DG et al.·Cerebellum
2023
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
Rare DisordersUndiagnosed DisordersDisorders of Unknown Prevalence

Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

RECRUITING
NCT01793168Sanford HealthStarted 2010-07

External Resources

Links to major genomics databases and tools