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…

Primary Disease Associations & Inheritance

Hemolytic anemia due to triosephosphate isomerase deficiencyMIM #615512

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Hemolytic anemia due to triosephosphate isomerase deficiency; no ClinGen or GenCC tier

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.73

LOEUF

Mechanism· predicted

📖

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

Background carrier burden — how many people carry a rare variant somewhere in TPI1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

362 rare PASS variants

Rare truncating (LoF)

1 in 2,800

66 rare PASS variants

Rare synonymous (reference)

1 in 310

167 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TPI1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 230	1 in 3,300
South Asian	~43k	1 in 160	1 in 1,300
Remaining (unassigned)	~30k	1 in 120	≈ 1 in 7,500
European (Finnish)	~27k	1 in 450	1 in 5,300
Admixed American	~22k	1 in 120	1 in 2,300
African / African American	~21k	1 in 140	1 in 2,000
East Asian	~20k	1 in 160	1 in 2,200
Ashkenazi Jewish	~13k	1 in 930	none seen
Middle Eastern	~2,884	1 in 110	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 7 coding exons well covered in gnomAD exomes and genomes.? see exons ↓