SLC25A46

Chr 5AR

solute carrier family 25 member 46

Also known as: HMSN6B, PCH1E

NCBI Gene: 91137ENSG00000164209UniProt: Q96AG3

This gene encodes a mitochondrial solute carrier protein family member. It functions in promoting mitochondrial fission, and prevents the formation of hyperfilamentous mitochondria. Mutation of this gene results in neuropathy and optic atrophy. [provided by RefSeq, Aug 2016]

Primary Disease Associations & Inheritance

Neuropathy, hereditary motor and sensory, type VIBMIM #616505
AR
Pontocerebellar hypoplasia, type 1EMIM #619303
AR
91
ClinVar variants
9
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— SLC25A46
🧬
Gene-Disease Validity (ClinGen)
Leigh syndrome · ARLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
9 Pathogenic / Likely Pathogenic· 37 VUS of 91 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.91LOEUF
pLI 0.000
Z-score 1.88
OE 0.55 (0.34–0.91)
Tolerant

Typical tolerance to LoF variation

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.
0.16Z-score
OE missense 0.97 (0.87–1.08)
219 obs / 225.8 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.0.55 (0.34–0.91)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.97 (0.87–1.08)
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.1.00
0≤1.21.6
LoF obs/exp: 11 / 20.1Missense obs/exp: 219 / 225.8Syn Z: 0.02

ClinVar Variant Classifications

91 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4
Likely Pathogenic5
VUS37
Likely Benign42
Benign2
Conflicting1
4
Pathogenic
5
Likely Pathogenic
37
VUS
42
Likely Benign
2
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
0
1
0
4
Likely Pathogenic
3
1
1
0
5
VUS
1
35
1
0
37
Likely Benign
0
0
16
26
42
Benign
0
0
2
0
2
Conflicting
—1
Total736212691

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

View in ClinVar →

Protein Context — Lollipop Plot

SLC25A46 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SLC25A46-related neuropathy, hereditary motor and sensory

definitive
ARLoss Of FunctionAbsent Gene Product
Eye
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Neuropathy, hereditary motor and sensory, type VIB

MIM #616505

Molecular basis of disorder known

Autosomal recessive

Pontocerebellar hypoplasia, type 1E

MIM #619303

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Insights into the genotype-phenotype correlation and molecular function of SLC25A46.
Abrams AJ et al.·Hum Mutat
2018Case report
Pontocerebellar Hypoplasia Type 1 and Associated Neuronopathies.
Škarica M et al.·Genes (Basel)
2025Review
Novel insights into SLC25A46-related pathologies in a genetic mouse model.
Terzenidou ME et al.·PLoS Genet
2017Functional
SLC-25A46 regulates mitochondrial fusion through the mitofusin protein FZO-1 and is essential for maintaining neuronal morphology.
Obinata H et al.·J Cell Sci
2025
Novel pathogenic SLC25A46 splice-site mutation causes an optic atrophy spectrum disorder.
Nguyen M et al.·Clin Genet
2017Case report
The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion.
Schuettpelz J et al.·Life Sci Alliance
2023
Loss of SLC25A46 causes neurodegeneration by affecting mitochondrial dynamics and energy production in mice.
Li Z et al.·Hum Mol Genet
2017
SLC25A46 mutations in patients with Parkinson's Disease and optic atrophy.
Bitetto G et al.·Parkinsonism Relat Disord
2020Case report
Loss of function of SLC25A46 causes lethal congenital pontocerebellar hypoplasia.
Wan J et al.·Brain
2016
Extension of the phenotype of biallelic loss-of-function mutations in SLC25A46 to the severe form of pontocerebellar hypoplasia type I.
Braunisch MC et al.·Clin Genet
2018
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

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