VPS37A

Chr 8

VPS37A subunit of ESCRT-I

Also known as: HCRP1, PQBP2, SPG53

NCBI Gene: 137492 ENSG00000155975 UniProt: Q8NEZ2

VPS37A encodes a component of the ESCRT-I complex that sorts ubiquitinated transmembrane proteins into multivesicular bodies for degradation. Mutations cause autosomal recessive spastic paraplegia-53, a hereditary spastic paraplegia primarily affecting the pyramidal motor system. The gene shows low constraint to loss-of-function variation (pLI 0.0007, LOEUF 0.722), consistent with its recessive inheritance pattern.

ResearchSummary from RefSeq, OMIM, UniProt

This gene belongs to the VPS37 family, and encodes a component of the ESCRT-I (endosomal sorting complex required for transport I) protein complex, required for the sorting of ubiquitinated transmembrane proteins into internal vesicles of multivesicular bodies. Expression of this gene is downregulated in hepatocellular carcinoma, and mutations in this gene are associated with autosomal recessive spastic paraplegia-53. A related pseudogene has been identified on chromosome 5. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2012]

ResearchGenerating clinical summary…

DNmechanismLOEUF 0.72

Clinical Summary— VPS37A

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Gene-Disease Validity (ClinGen)

complex hereditary spastic paraplegia · ARLimited

Limited evidence — not for standalone diagnostic reporting

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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

1 unique Pathogenic / Likely Pathogenic· 200 VUS of 342 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.72LOEUF

pLI 0.001

Z-score 2.53

OE 0.41 (0.25–0.72)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.88Z-score

OE missense 1.18 (1.06–1.31)

235 obs / 199.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.41 (0.25–0.72)

0≤0.351.4

Missense OE?1.18 (1.06–1.31)

0≤0.61.4

Synonymous OE?1.27

0≤1.21.6

LoF obs/exp: 9 / 21.7Missense obs/exp: 235 / 199.8Syn Z: -1.82

This gene — mechanism propensity

0.6744th %ile

GOF

0.4874th %ile

LOF

0.2678th %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

342 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS200

Likely Benign94

Benign27

Conflicting4

Pathogenic

200

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	0	0	0	0	0
VUS	3	189	5	3	200
Likely Benign	2	7	51	34	94
Benign	0	1	24	2	27
Conflicting	—				4
Total	5	198	80	39	326

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

View in ClinVar →

80 pathogenic / likely-pathogenic (of 94) ClinVar copy-number / structural variants overlap VPS37A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →