Is MVK p.Pro263= (c.789C>A) pathogenic?

MVK p.Pro263= (c.789C>A) is classified Benign/Likely benign in MVK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-06). Very rare (popmax 0.00161%, nfe); Associated with hyperimmunoglobulinemia D with periodic fever.

What condition is associated with MVK p.Pro263= (c.789C>A)?

MVK p.Pro263= (c.789C>A) is associated with hyperimmunoglobulinemia D with periodic fever, porokeratosis 3, disseminated superficial actinic type, mevalonic aciduria (ClinVar).

How common is MVK p.Pro263= (c.789C>A) in the general population?

MVK p.Pro263= (c.789C>A) is very rare (popmax 0.00161%, nfe) (gnomAD).

How is Mevalonate kinase deficiency inherited?

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

MVK p.Pro263=

c.789C>A · rs146181903 · VCV1143237

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00161%, 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 -9.8	GERP -3.3
Overall
CADD	0.028	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00161% European (non-Finnish) · 19/1,180,056 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00118% 19/1,614,104 alleles · very rare exomes 17/1,461,876 · genomes 2/152,228 · joint denominator

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.Pro263=
Coding: c.789C>A
MANE Select: NM_000431
dbSNP: rs146181903
Type: single nucleotide variant
Location: chr12:109591261 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.31 · 1 PDB
Residue 263: an α-helix

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 p.Pro263Arg Uncertain significance ★★ ⚠ same residue
MVK p.Pro263Ser 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

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-pro263 (accessed [today's date]).

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