MPC1

Chr 6AR

mitochondrial pyruvate carrier 1

Also known as: BRP44L, CGI-129, MPYCD, SLC54A1

NCBI Gene: 51660 ENSG00000060762 UniProt: Q9Y5U8 OMIM: 614738

The encoded protein forms a heterodimer with MPC2 in the inner mitochondrial membrane to transport pyruvate into mitochondria, maintaining the balance between glycolysis and oxidative phosphorylation. Mutations cause mitochondrial pyruvate carrier deficiency, an autosomal recessive disorder affecting cellular metabolism. The gene shows tolerance to loss-of-function variants (pLI 0.04, LOEUF 1.19), consistent with the recessive inheritance pattern.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is part of an MPC1/MPC2 heterodimer that is responsible for transporting pyruvate into mitochondria. The encoded protein is found in the inner mitochondrial membrane. Defects in this gene are a cause of mitochondrial pyruvate carrier deficiency. Several transcript variants, some protein coding and one non-protein coding, have been found for this gene. [provided by RefSeq, Aug 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.191 OMIM phenotype

Clinical Summary— MPC1

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.04) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 18 VUS of 66 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MPC1

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?

1.19LOEUF

pLI 0.038

Z-score 1.28

OE 0.46 (0.21–1.19)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.07Z-score

OE missense 0.62 (0.48–0.81)

40 obs / 64.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.46 (0.21–1.19)

0≤0.351.4

Missense OE?0.62 (0.48–0.81)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 3 / 6.5Missense obs/exp: 40 / 64.2Syn Z: -0.09

This gene — mechanism propensity

0.85top 10%

GOF

0.73top 25%

LOF

0.2580th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-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

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

66 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic4

VUS18

Likely Benign17

Benign15

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	0	0	2
Likely Pathogenic	0	4	0	0	4
VUS	2	15	1	0	18
Likely Benign	0	2	8	7	17
Benign	0	1	13	1	15
Total	2	24	22	8	56

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

View in ClinVar →

53 pathogenic / likely-pathogenic (of 60) ClinVar copy-number / structural variants overlap MPC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →