TPI1

Chr 12AR

triosephosphate isomerase 1

Also known as: HEL-S-49, TIM, TPI, TPID

NCBI Gene: 7167 ENSG00000111669 UniProt: P60174 OMIM: 190450

The protein functions as triosephosphate isomerase, catalyzing the interconversion between dihydroxyacetone phosphate and glyceraldehyde-3-phosphate in glycolysis and gluconeogenesis. Mutations cause triosephosphate isomerase deficiency, which presents as hemolytic anemia and follows autosomal recessive inheritance. This is a severe metabolic disorder that typically manifests in infancy with progressive neurological deterioration in addition to the hematologic features.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an enzyme, consisting of two identical proteins, which catalyzes the isomerization of glyceraldehydes 3-phosphate (G3P) and dihydroxy-acetone phosphate (DHAP) in glycolysis and gluconeogenesis. Mutations in this gene are associated with triosephosphate isomerase deficiency. Pseudogenes have been identified on chromosomes 1, 4, 6 and 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.731 OMIM phenotype

Clinical Summary— TPI1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.35) despite low pLI — interpret in context.

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ClinVar Variants

12 unique Pathogenic / Likely Pathogenic· 79 VUS of 182 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TPI1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.73LOEUF

pLI 0.030

Z-score 2.29

OE 0.35 (0.18–0.73)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.22Z-score

OE missense 1.05 (0.93–1.19)

167 obs / 159.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.35 (0.18–0.73)

0≤0.351.4

Missense OE?1.05 (0.93–1.19)

0≤0.61.4

Synonymous OE?1.28

0≤1.21.6

LoF obs/exp: 5 / 14.3Missense obs/exp: 167 / 159.1Syn Z: -1.75

This gene — mechanism propensity

0.6842th %ile

GOF

0.5170th %ile

LOF

0.3259th %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

182 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic5

VUS79

Likely Benign62

Benign12

Conflicting11

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	3	3	1	0	7
Likely Pathogenic	3	2	0	0	5
VUS	2	66	11	0	79
Likely Benign	0	0	33	29	62
Benign	0	0	10	2	12
Conflicting	—				11
Total	8	71	55	31	176

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

View in ClinVar →

46 pathogenic / likely-pathogenic (of 61) ClinVar copy-number / structural variants overlap TPI1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →