SLC41A3

Chr 3

solute carrier family 41 member 3

Also known as: SLC41A1-L2

NCBI Gene: 54946 ENSG00000114544 UniProt: Q96GZ6 OMIM: 610803

This protein functions as a sodium/magnesium ion exchanger that mediates magnesium efflux from mitochondria across the inner mitochondrial membrane. Mutations cause autosomal recessive early-onset mitochondrial encephalomyopathy with seizures, developmental delay, and lactic acidosis. The gene shows low constraint against loss-of-function variants, consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

Enables magnesium:sodium antiporter activity. Involved in mitochondrial magnesium ion transmembrane transport. Located in mitochondrial inner membrane and plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.29

Clinical Summary— SLC41A3

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

64 VUS of 106 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.29LOEUF

pLI 0.000

Z-score 0.48

OE 0.89 (0.63–1.29)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.59Z-score

OE missense 0.90 (0.81–1.00)

253 obs / 281.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.89 (0.63–1.29)

0≤0.351.4

Missense OE?0.90 (0.81–1.00)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 21 / 23.5Missense obs/exp: 253 / 281.0Syn Z: 0.87

This gene — mechanism propensity

0.6939th %ile

GOF

0.6638th %ile

LOF

0.3452th %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

106 submitted variants in ClinVar

ClinVar

Classification Summary

VUS64

Likely Benign7

Benign14

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	64	0	0	64
Likely Benign	7	0	0	7
Benign	0	13	1	14
Total	71	13	1	85

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap SLC41A3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →