SLC25A19

Chr 17AR

solute carrier family 25 member 19

Also known as: DNC, MCPHA, MTPPT, MUP1, THMD3, THMD4, TPC

NCBI Gene: 60386UniProt: Q9HC21

This gene encodes a mitochondrial protein that is a member of the solute carrier family. Although this protein was initially thought to be the mitochondrial deoxynucleotide carrier involved in the uptake of deoxynucleotides into the matrix of the mitochondria, further studies have demonstrated that this protein instead functions as the mitochondrial thiamine pyrophosphate carrier, which transports thiamine pyrophosphates into mitochondria. Mutations in this gene cause microcephaly, Amish type, a metabolic disease that results in severe congenital microcephaly, severe 2-ketoglutaric aciduria, and death within the first year. Multiple alternatively spliced variants, encoding the same protein, have been identified for this gene. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Microcephaly, Amish typeMIM #607196
AR
Thiamine metabolism dysfunction syndrome 4 (progressive polyneuropathy type)MIM #613710
AR
0
Active trials
225
ClinVar variants
26
Pathogenic / LP
0.6
Missense Z
0.52
LOEUF
6
Pubs (2 yr)
Clinical Summary— SLC25A19
🧬
Gene-Disease Validity (ClinGen)
Leigh syndrome · ARLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.65) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
26 Pathogenic / Likely Pathogenic· 95 VUS of 225 total submissions
📖
GeneReview available — SLC25A19
Authoritative clinical overview · Recommended first read
Open GeneReview ↗
Some data sources returned errors (1)

ensembl: TimeoutError: The operation was aborted due to timeout

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.52LOEUF
pLI 0.649
Z-score 2.68
OE 0.17 (0.07–0.52)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.59Z-score
OE missense 0.88 (0.78–1.00)
171 obs / 194.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.17 (0.07–0.52)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.88 (0.78–1.00)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.92
0≤1.21.6
LoF obs/exp: 2 / 12.0Missense obs/exp: 171 / 194.0Syn Z: 0.54

ClinVar Variant Classifications

225 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22
Likely Pathogenic4
VUS95
Likely Benign63
Benign28
Conflicting13
22
Pathogenic
4
Likely Pathogenic
95
VUS
63
Likely Benign
28
Benign
13
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
10
11
0
22
Likely Pathogenic
0
3
1
0
4
VUS
2
70
23
0
95
Likely Benign
0
4
29
30
63
Benign
0
0
26
2
28
Conflicting
—13
Total3879032225

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

View in ClinVar →

Protein Context — Lollipop Plot

SLC25A19 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SLC25A19-related Amish lethal microcephaly

strong
ARUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Microcephaly, Amish type

MIM #607196

Molecular basis of disorder known

Autosomal recessive

Thiamine metabolism dysfunction syndrome 4 (progressive polyneuropathy type)

MIM #613710

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
SLC25A19 deficiency and bilateral striatal necrosis with polyneuropathy: a new case and review of the literature.
Porta F et al.·J Pediatr Endocrinol Metab
2020Review
SLC25A19 is a novel prognostic biomarker related to immune invasion and ferroptosis in HCC.
Liu S et al.·Int Immunopharmacol
2024
The evidence that the DNC (SLC25A19) is not the mitochondrial deoxyribonucleotide carrier.
Kang J et al.·Mitochondrion
2008Review
SLC25A19 drives colorectal cancer progression by regulating p53.
Jiang J et al.·Cancer Med
2024
Comprehensive analysis of mitochondrial solute carrier family 25 (SLC25) identifies member 19 (SLC25A19) as a regulatory factor in hepatocellular carcinoma.
Gao X et al.·Gene
2025
Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4.
Chen Y et al.·Orphanet J Rare Dis
2021Case report
Functional analysis of the third identified SLC25A19 mutation causative for the thiamine metabolism dysfunction syndrome 4.
Bottega R et al.·J Hum Genet
2019Case report
Treatment of genetic defects of thiamine transport and metabolism.
Ortigoza-Escobar JD et al.·Expert Rev Neurother
2016Review
Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies.
Marcé-Grau A et al.·J Inherit Metab Dis
2019Review
SLC25A19 mutation as a cause of neuropathy and bilateral striatal necrosis.
Spiegel R et al.·Ann Neurol
2009
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 4 full-text resultsSearch PubTator3 ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients