Is VMA21 p.Pro4= (c.12G>A) pathogenic?

VMA21 p.Pro4= (c.12G>A) is classified Likely benign in VMA21 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-10). Very rare (popmax 0.00178%, afr); Associated with X-linked myopathy with excessive autophagy.

What condition is associated with VMA21 p.Pro4= (c.12G>A)?

VMA21 p.Pro4= (c.12G>A) is associated with X-linked myopathy with excessive autophagy (ClinVar).

How common is VMA21 p.Pro4= (c.12G>A) in the general population?

VMA21 p.Pro4= (c.12G>A) is very rare (popmax 0.00178%, afr) (gnomAD).

How is X-linked myopathy with excessive autophagy inherited?

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

VMA21 p.Pro4=

c.12G>A · rs1029458335 · VCV772933

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00178%, afr)

Conditions

X-linked myopathy with excessive autophagy

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 -1.1	GERP -3.6, phastCons 0.001
Overall
CADD	5.092	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00178% African / African-American · 1/56,178 alleles

Filtering AF 9.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000345% 4/1,160,983 alleles · very rare exomes 3/1,047,754 · genomes 1/113,229 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00178%	56,178
European (non-Finnish)	0.000344%	290,817

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: VMA21
Protein: p.Pro4=
Coding: c.12G>A
MANE Select: NM_001017980
dbSNP: rs1029458335
Type: single nucleotide variant
Location: chrX:151397320 (GRCh38)
Structure: AlphaFold pLDDT 70.41

Full VMA21 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

X-linked myopathy with excessive autophagy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For X-linked myopathy with excessive autophagy (Orphanet):

Inheritance: X-linked recessive
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal

Similar variants

VMA21 p.Pro4Arg Uncertain significance ★ ⚠ same residue
VMA21 p.Pro4Gln Uncertain significance ★ ⚠ same residue
VMA21 p.Pro4Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
VMA21 c.163+4A>G Pathogenic ★★ same condition
VMA21 c.53+5C>T Uncertain significance ★★ same condition
VMA21 p.Ala56Thr Uncertain significance ★★ ⚠ same condition
VMA21 p.Ala68Ser Uncertain significance ★★ ⚠ same condition
VMA21 p.Ala75Thr 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/vma21-p-pro4 (accessed [today's date]).

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