TMEFF1

Chr 9

transmembrane protein with EGF like and two follistatin like domains 1

Also known as: C9orf2, CT120.1, H7365, TR-1

NCBI Gene: 8577ENSG00000241697UniProt: Q8IYR6OMIM: 603421

The TMEFF1 protein functions as a neuron-specific restriction factor that prevents herpes simplex virus infection in the brain by blocking viral entry through inhibition of viral glycoprotein binding to cellular receptors. Loss-of-function mutations cause increased susceptibility to herpes simplex encephalitis with autosomal recessive inheritance. The pathogenic mechanism involves loss of the protein's ability to prevent viral glycoproteins from associating with their cellular receptors, particularly blocking HSV-1 glycoprotein D binding to NECTIN1.

OMIMResearchSummary from RefSeq, UniProt
DNmechanismLOEUF 0.47
Clinical Summary— TMEFF1
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.54) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
33 unique Pathogenic / Likely Pathogenic· 19 VUS of 52 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.47LOEUF
pLI 0.538
Z-score 3.26
OE 0.20 (0.10–0.47)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
1.10Z-score
OE missense 0.78 (0.68–0.89)
148 obs / 190.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.20 (0.10–0.47)
0≤0.351.4
Missense OE0.78 (0.68–0.89)
0≤0.61.4
Synonymous OE0.92
0≤1.21.6
LoF obs/exp: 4 / 19.6Missense obs/exp: 148 / 190.6Syn Z: 0.53
DN
0.6162th %ile
GOF
0.5955th %ile
LOF
0.49top 25%

The highest-scoring mechanism for this gene is dominant-negative.

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

52 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic31
Likely Pathogenic2
VUS19
31
Pathogenic
2
Likely Pathogenic
19
VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
31
0
31
Likely Pathogenic
0
0
2
0
2
VUS
0
14
5
0
19
Likely Benign
0
0
0
0
0
Benign
0
0
0
0
0
Total01438052

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

View in ClinVar →

Protein Context — Lollipop Plot

TMEFF1 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 4 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients