Is MKKS p.Val458Phe (c.1372G>T) pathogenic?

MKKS p.Val458Phe (c.1372G>T) is classified Uncertain significance in MKKS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-07). AlphaMissense: ambiguous (0.4122); Absent from gnomAD v4.1; Associated with Bardet-Biedl syndrome.

What condition is associated with MKKS p.Val458Phe (c.1372G>T)?

MKKS p.Val458Phe (c.1372G>T) is associated with Bardet-Biedl syndrome, McKusick-Kaufman syndrome (ClinVar).

How common is MKKS p.Val458Phe (c.1372G>T) in the general population?

MKKS p.Val458Phe (c.1372G>T) is absent from gnomAD v4.1 (gnomAD).

How is Bardet-Biedl syndrome inherited?

Typically Autosomal recessive, Oligogenic (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MKKS p.Val458Phe (c.1372G>T)?

AlphaMissense predicts ambiguous (score 0.4122) — an in-silico prediction, not a clinical call.

MKKS p.Val458Phe

c.1372G>T · rs1600843195 · VCV649205

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4122 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
AlphaMissense	0.4122	ambiguous
REVEL	0.368	indeterminate
SaProt	LLR -10.22	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.39, phastCons 0.98
Regional constraint	o/e 1.00	unconstrained · MANE · 8,264 bp · p 0.96 · regional, not allelic
Overall
CADD	21.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MKKS
Protein: p.Val458Phe
Coding: c.1372G>T
MANE Select: NM_170784
dbSNP: rs1600843195
Type: single nucleotide variant
Location: chr20:10405588 (GRCh38)
Gene constraint: LOEUF 1.112 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.05
Residue 458: a UniProt-annotated variant site (in bbs6)

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

Disease context

Bardet-Biedl syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: McKusick-Kaufman syndrome

For Bardet-Biedl syndrome (Orphanet):

Inheritance: Autosomal recessive, Oligogenic
Onset: Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Specific population)

Similar variants

MKKS c.986-1G>A Pathogenic ★★ same condition
MKKS p.Arg139Ter Pathogenic/Likely pathogenic ★★ same condition
MKKS p.Gln391Ter Pathogenic/Likely pathogenic ★★ same condition
MKKS p.Gln59Ter Pathogenic/Likely pathogenic ★★ same condition
MKKS p.Gly345Glu Pathogenic/Likely pathogenic ★★ same condition
MKKS p.Gly52Asp Pathogenic/Likely pathogenic ★★ same condition
MKKS p.His84Tyr Pathogenic/Likely pathogenic ★★ ⚠ same condition
MKKS p.Leu74Ter 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/mkks-p-val458phe (accessed [today's date]).

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