SFXN4

Chr 10AR

sideroflexin 4

Also known as: BCRM1, COXPD18, SLC56A4

NCBI Gene: 119559 ENSG00000183605 UniProt: Q6P4A7 OMIM: 615564

The protein is a mitochondrial amino acid transporter located in the inner mitochondrial membrane that is required for mitochondrial respiratory homeostasis and erythropoiesis. Autosomal recessive mutations cause combined oxidative phosphorylation deficiency 18, which presents as mitochondriopathy with macrocytic anemia. The gene shows low constraint against loss-of-function variants (pLI near 0), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the sideroflexin family. The encoded protein is a transmembrane protein of the inner mitochondrial membrane, and is required for mitochondrial respiratory homeostasis and erythropoiesis. Mutations in this gene are associated with mitochondriopathy and macrocytic anemia. Alternatively spliced transcript variants have been found in this gene. [provided by RefSeq, Jan 2014]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.911 OMIM phenotype

Clinical Summary— SFXN4

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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 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

16 unique Pathogenic / Likely Pathogenic· 41 VUS of 223 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?

0.91LOEUF

pLI 0.000

Z-score 1.90

OE 0.59 (0.40–0.91)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.77Z-score

OE missense 0.84 (0.74–0.96)

156 obs / 185.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.59 (0.40–0.91)

0≤0.351.4

Missense OE?0.84 (0.74–0.96)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 15 / 25.3Missense obs/exp: 156 / 185.3Syn Z: 0.33

This gene — mechanism propensity

0.7325th %ile

GOF

0.5268th %ile

LOF

0.2484th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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

223 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic10

VUS41

Likely Benign79

Benign60

Conflicting7

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	0	0	0	6
Likely Pathogenic	9	0	1	0	10
VUS	0	40	1	0	41
Likely Benign	0	8	54	17	79
Benign	0	0	53	7	60
Conflicting	—				7
Total	15	48	109	24	203

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

View in ClinVar →

29 pathogenic / likely-pathogenic (of 38) ClinVar copy-number / structural variants overlap SFXN4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →