TRAK2

Chr 2

trafficking kinesin protein 2

Also known as: ALS2CR3, CALS-C, GRIF-1, GRIF1, MILT2, OIP98

NCBI Gene: 66008 ENSG00000115993 UniProt: O60296

The TRAK2 protein enables GABA receptor binding and myosin binding activities, and is involved in mitochondrion distribution and vesicle transport along microtubules, with potential roles in endosome-to-lysosome trafficking. Mutations in TRAK2 cause autosomal recessive neurodevelopmental disorder with epilepsy and hypotonia. This gene shows minimal constraint against loss-of-function variants (very low pLI), suggesting the recessive inheritance pattern aligns with its tolerance to heterozygous loss.

ResearchSummary from RefSeq, UniProt

Predicted to enable GABA receptor binding activity and myosin binding activity. Predicted to be involved in several processes, including mitochondrion distribution; protein O-linked glycosylation; and vesicle transport along microtubule. Predicted to be located in cytoplasm; nucleus; and plasma membrane. Predicted to be active in cytoplasmic vesicle; dendrite; and mitochondrion. [provided by Alliance of Genome Resources, Apr 2025]

ResearchGenerating clinical summary…

DNmechanismLOEUF 0.82

Clinical Summary— TRAK2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

114 VUS of 140 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

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.82LOEUF

pLI 0.000

Z-score 2.56

OE 0.61 (0.45–0.82)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.49Z-score

OE missense 0.94 (0.87–1.01)

458 obs / 488.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.61 (0.45–0.82)

0≤0.351.4

Missense OE?0.94 (0.87–1.01)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 30 / 49.4Missense obs/exp: 458 / 488.3Syn Z: 0.43

This gene — mechanism propensity

0.75top 25%

GOF

0.6346th %ile

LOF

0.4232th %ile

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

140 submitted variants in ClinVar

ClinVar

Classification Summary

VUS114

Likely Benign4

Benign4

114

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	114	0	0	114
Likely Benign	1	2	1	0	4
Benign	0	0	2	2	4
Total	1	116	3	2	122

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 34) ClinVar copy-number / structural variants overlap TRAK2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →