Is MVK p.Ser267Pro (c.799T>C) pathogenic?

MVK p.Ser267Pro (c.799T>C) is classified Likely pathogenic in MVK (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-19). AlphaMissense: likely pathogenic (0.9231); Very rare (popmax 8.47e-05%, nfe); Associated with hyperimmunoglobulinemia D with periodic fever.

What condition is associated with MVK p.Ser267Pro (c.799T>C)?

MVK p.Ser267Pro (c.799T>C) is associated with hyperimmunoglobulinemia D with periodic fever, porokeratosis 3, disseminated superficial actinic type, mevalonic aciduria (ClinVar).

How common is MVK p.Ser267Pro (c.799T>C) in the general population?

MVK p.Ser267Pro (c.799T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Mevalonate kinase deficiency inherited?

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

What do computational predictors say about MVK p.Ser267Pro (c.799T>C)?

AlphaMissense predicts likely pathogenic (score 0.9231) — an in-silico prediction, not a clinical call.

MVK p.Ser267Pro

c.799T>C · rs1885666876 · VCV1044056

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9231 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperimmunoglobulinemia D with periodic fever

Computational evidence

Protein change
AlphaMissense	0.9231	likely pathogenic ✓ concordant with ClinVar · top 7% in MVK
REVEL	0.897	moderately pathogenic-leaning
SaProt	LLR -12.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 22 kb · p 1.2e-06 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,020 alleles

Overall 6.2e-05% 1/1,614,130 alleles · very rare exomes 1/1,461,884 · genomes 0/152,246 · 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.Ser267Pro
Coding: c.799T>C
MANE Select: NM_000431
dbSNP: rs1885666876
Type: single nucleotide variant
Location: chr12:109591271 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.31 · 1 PDB
Residue 267: 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.Ser267Ala 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-ser267pro (accessed [today's date]).

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