TMEM240

Chr 1AD

transmembrane protein 240

Also known as: C1orf70, SCA21

NCBI Gene: 339453 ENSG00000205090 UniProt: Q5SV17 OMIM: 616101

The protein is a transmembrane domain-containing protein expressed in the brain and cerebellum. Mutations cause spinocerebellar ataxia 21, a progressive neurodegenerative disorder primarily affecting cerebellar function and coordination. This condition follows autosomal dominant inheritance.

OMIM ResearchSummary from RefSeq, OMIM

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.871 OMIM phenotype

Clinical Summary— TMEM240

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 77 VUS of 158 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.87LOEUF

pLI 0.229

Z-score 1.80

OE 0.28 (0.11–0.87)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.55Z-score

OE missense 0.58 (0.47–0.72)

62 obs / 107.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.28 (0.11–0.87)

0≤0.351.4

Missense OE?0.58 (0.47–0.72)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 2 / 7.2Missense obs/exp: 62 / 107.0Syn Z: -0.55

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTMEM240-related spinocerebellar ataxia and intellectual disabilityLOFAD

This gene — mechanism propensity

0.6939th %ile

GOF

0.78top 25%

LOF

0.3745th %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

158 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic2

VUS77

Likely Benign52

Benign17

Conflicting8

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	0	2	0	0	2
VUS	5	67	5	0	77
Likely Benign	0	5	18	29	52
Benign	0	1	10	6	17
Conflicting	—				8
Total	6	75	33	35	157

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

View in ClinVar →

134 pathogenic / likely-pathogenic (of 155) ClinVar copy-number / structural variants overlap TMEM240 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →