SPG7

Chr 16AR

SPG7 matrix AAA peptidase subunit, paraplegin

Also known as: CAR, CMAR, PGN, SPG5C

NCBI Gene: 6687 ENSG00000197912 UniProt: Q9UQ90 OMIM: 607259

The protein is a mitochondrial metalloprotease that functions in the inner mitochondrial membrane and belongs to the AAA family involved in proteolysis, protein folding, and organelle biogenesis. Mutations cause autosomal recessive spastic paraplegia 7, characterized by progressive spasticity and weakness of the lower limbs. The pathogenic mechanism involves dominant negative effects disrupting normal mitochondrial protease function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a mitochondrial metalloprotease protein that is a member of the AAA family. Members of this protein family share an ATPase domain and have roles in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis. Mutations in this gene cause autosomal recessive spastic paraplegia 7. Two transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Mar 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 1.652 OMIM phenotypes

Clinical Summary— SPG7

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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

219 unique Pathogenic / Likely Pathogenic· 528 VUS of 1284 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SPG7

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.65LOEUF

pLI 0.000

Z-score -1.69

OE 1.30 (1.03–1.65)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.87Z-score

OE missense 1.11 (1.03–1.20)

528 obs / 474.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.30 (1.03–1.65)

0≤0.351.4

Missense OE?1.11 (1.03–1.20)

0≤0.61.4

Synonymous OE?1.38

0≤1.21.6

LoF obs/exp: 48 / 36.9Missense obs/exp: 528 / 474.5Syn Z: -4.22

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSPG7-related spastic paraplegiaOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.76top 25%

GOF

0.5661th %ile

LOF

0.3744th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

1284 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic101

Likely Pathogenic118

VUS528

Likely Benign357

Benign70

Conflicting91

101

Pathogenic

118

Likely Pathogenic

528

VUS

357

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	64	6	31	0	101
Likely Pathogenic	82	34	2	0	118
VUS	12	449	52	15	528
Likely Benign	0	4	188	165	357
Benign	0	4	61	5	70
Conflicting	—				91
Total	158	497	334	185	1,265

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

View in ClinVar →

57 pathogenic / likely-pathogenic (of 96) ClinVar copy-number / structural variants overlap SPG7 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →