Is VPS37A p.Arg53= (c.157A>C) pathogenic?

VPS37A p.Arg53= (c.157A>C) is classified Likely benign in VPS37A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-27). Very rare (popmax 0.00133%, afr); Associated with hereditary spastic paraplegia 53.

What condition is associated with VPS37A p.Arg53= (c.157A>C)?

VPS37A p.Arg53= (c.157A>C) is associated with hereditary spastic paraplegia 53 (ClinVar).

How common is VPS37A p.Arg53= (c.157A>C) in the general population?

VPS37A p.Arg53= (c.157A>C) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Autosomal recessive spastic paraplegia type 53 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

VPS37A p.Arg53=

c.157A>C · rs777788040 · VCV2072400

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

hereditary spastic paraplegia 53

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.2	GERP 2.5, phastCons 1
Overall
CADD	12.45	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,918 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000806% 13/1,613,364 alleles · very rare exomes 10/1,461,140 · genomes 3/152,224 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,918
European (non-Finnish)	0.00102%	98,309

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: VPS37A
Protein: p.Arg53=
Coding: c.157A>C
MANE Select: NM_152415
dbSNP: rs777788040
Type: single nucleotide variant
Location: chr8:17265938 (GRCh38)
Gene constraint: LOEUF 0.853 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.48 · 1 PDB
Residue 53: a β-strand

Full VPS37A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 53 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive spastic paraplegia type 53 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

VPS37A p.Ala176Ser Uncertain significance ★★ ⚠ same condition
VPS37A p.Ala193Thr Uncertain significance ★★ ⚠ same condition
VPS37A p.Ala388Ser Uncertain significance ★★ ⚠ same condition
VPS37A p.Ala44Asp Uncertain significance ★★ ⚠ same condition
VPS37A p.Asp268Asn Uncertain significance ★★ ⚠ same condition
VPS37A p.Asp271Gly Uncertain significance ★★ ⚠ same condition
VPS37A p.Glu249Lys Uncertain significance ★★ ⚠ same condition
VPS37A p.Glu302Lys Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/vps37a-p-arg53 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown