TRAK1

Chr 3

trafficking kinesin protein 1

Also known as: DEE68, EIEE68, MILT1, OIP106

NCBI Gene: 22906 ENSG00000182606 UniProt: Q9UPV9

TRAK1 encodes a protein that regulates endosome-to-lysosome trafficking and mitochondrial transport by forming complexes that link mitochondria to motor proteins for cellular movement. Mutations cause developmental and epileptic encephalopathy 68, inherited in an autosomal recessive pattern. The gene is highly constrained against loss-of-function variants (LOEUF 0.52), suggesting that complete loss of protein function is poorly tolerated.

ResearchSummary from RefSeq, OMIM, UniProt

Predicted to enable GABA receptor binding activity and myosin binding activity. Involved in endosome to lysosome transport. Located in early endosome and mitochondrion. Implicated in developmental and epileptic encephalopathy 68. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.52

Clinical Summary— TRAK1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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ClinVar Variants

9 unique Pathogenic / Likely Pathogenic· 199 VUS of 382 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.52LOEUF

pLI 0.000

Z-score 4.02

OE 0.33 (0.22–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.09Z-score

OE missense 0.87 (0.81–0.94)

516 obs / 590.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.33 (0.22–0.52)

0≤0.351.4

Missense OE?0.87 (0.81–0.94)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 14 / 42.2Missense obs/exp: 516 / 590.8Syn Z: -1.14

This gene — mechanism propensity

0.77top 25%

GOF

0.7029th %ile

LOF

0.4234th %ile

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

DNprediction above median

GOFprediction above median

LOF100% of P/LP variants are LoF

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

382 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic4

VUS199

Likely Benign111

Benign33

Conflicting2

Pathogenic

Likely Pathogenic

199

VUS

111

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	0	0	0	5
Likely Pathogenic	4	0	0	0	4
VUS	1	191	5	2	199
Likely Benign	0	14	26	71	111
Benign	0	8	15	10	33
Conflicting	—				2
Total	10	213	46	83	354

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

View in ClinVar →

7 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap TRAK1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →