Is MVK p.Asp99= (c.297C>T) pathogenic?

MVK p.Asp99= (c.297C>T) is classified Likely benign in MVK (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-12). Ultra-rare (popmax 0.0125%, nfe); Associated with hyperimmunoglobulinemia D with periodic fever.

What condition is associated with MVK p.Asp99= (c.297C>T)?

MVK p.Asp99= (c.297C>T) is associated with hyperimmunoglobulinemia D with periodic fever, porokeratosis 3, disseminated superficial actinic type, mevalonic aciduria (ClinVar).

How common is MVK p.Asp99= (c.297C>T) in the general population?

MVK p.Asp99= (c.297C>T) is ultra-rare (popmax 0.0125%, nfe) (gnomAD).

How is Mevalonate kinase deficiency inherited?

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

MVK p.Asp99=

c.297C>T · rs376323791 · VCV736383

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0125%, nfe)

Conditions

hyperimmunoglobulinemia D with periodic fever

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.43	GERP -3.6, phastCons 0.015
Overall
CADD	7.153	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0125% European (non-Finnish) · 147/1,180,056 alleles

Filtering AF 0.0108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.00966% 156/1,614,114 alleles · ultra-rare exomes 150/1,461,888 · genomes 6/152,226 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0125%	8,028
Remaining individualsnot grpmax-eligible	0.0048%	20,830
Finnishnot grpmax-eligible	0.00312%	32,017
South Asian	0.0022%	45,544
Admixed American	0.00167%	60,006
African / African-American	0.00133%	74,940

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.Asp99=
Coding: c.297C>T
MANE Select: NM_000431
dbSNP: rs376323791
Type: single nucleotide variant
Location: chr12:109579872 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.31 · 1 PDB

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

Disease context

hyperimmunoglobulinemia D with periodic fever — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: porokeratosis 3, disseminated superficial actinic type mevalonic aciduria

For Mevalonate kinase deficiency (Orphanet):

Inheritance: Not applicable
Onset: Infancy

Similar variants

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
MVK p.Arg215Gln Pathogenic/Likely 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-asp99 (accessed [today's date]).

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