Is MVK p.Pro288= (c.864G>A) pathogenic?

MVK p.Pro288= (c.864G>A) is classified Likely benign in MVK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-12). Ultra-rare (popmax 0.0373%, sas); Associated with mevalonic aciduria.

How common is MVK p.Pro288= (c.864G>A) in the general population?

MVK p.Pro288= (c.864G>A) is ultra-rare (popmax 0.0373%, sas) (gnomAD).

How is Mevalonate kinase deficiency inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

MVK p.Pro288=

Q: What condition is associated with MVK p.Pro288= (c.864G>A)?

MVK p.Pro288= (c.864G>A) is associated with mevalonic aciduria, porokeratosis 3, disseminated superficial actinic type, hyperimmunoglobulinemia D with periodic fever (ClinVar).

c.864G>A · rs149708247 · VCV536577

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0373%, sas)

Conditions

mevalonic aciduria

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 -4.8	GERP -3.3
Overall
CADD	0.743	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0373% South Asian · 34/91,088 alleles

Filtering AF 0.0274% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.024%

Overall 0.00812% 131/1,614,172 alleles · ultra-rare exomes 122/1,461,822 · genomes 9/152,350 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0373%	2,679
Remaining individualsnot grpmax-eligible	0.0112%	8,930
European (non-Finnish)	0.00737%	13,564
East Asian	0.00223%	44,878
Admixed American	0.00167%	60,030
Finnishnot grpmax-eligible	0.00156%	63,994

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: MVK
Protein: p.Pro288=
Coding: c.864G>A
MANE Select: NM_000431
dbSNP: rs149708247
Type: single nucleotide variant
Location: chr12:109591336 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.31 · 1 PDB
Residue 288: an α-helix

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

Disease context

mevalonic aciduria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: porokeratosis 3, disseminated superficial actinic type hyperimmunoglobulinemia D with periodic fever

For Mevalonate kinase deficiency (Orphanet):

Inheritance: Not applicable
Onset: Infancy

Similar variants

MVK p.Pro288Leu Uncertain significance ★★ ⚠ same residue
MVK c.1039+1G>C Likely pathogenic ★★ same condition
MVK c.677+1G>A Likely pathogenic ★★ same condition
MVK c.78+1G>A Likely pathogenic ★★ same condition
MVK c.79-2A>G Likely pathogenic ★★ same condition
MVK p.Ala147Thr Likely pathogenic ★★ same condition
MVK p.Ala148Thr Pathogenic/Likely pathogenic ★★ same condition
MVK p.Ala334Thr Pathogenic ★★ 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/mvk-p-pro288 (accessed [today's date]).

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