Is MKKS p.Leu26Val (c.76C>G) pathogenic?

MKKS p.Leu26Val (c.76C>G) is classified Uncertain significance in MKKS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-28). AlphaMissense: likely benign (0.0931); Very rare (popmax 0.00167%, amr); Associated with Bardet-Biedl syndrome.

What condition is associated with MKKS p.Leu26Val (c.76C>G)?

MKKS p.Leu26Val (c.76C>G) is associated with Bardet-Biedl syndrome, McKusick-Kaufman syndrome (ClinVar).

How common is MKKS p.Leu26Val (c.76C>G) in the general population?

MKKS p.Leu26Val (c.76C>G) is very rare (popmax 0.00167%, amr) (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.Leu26Val (c.76C>G)?

AlphaMissense predicts likely benign (score 0.0931) — an in-silico prediction, not a clinical call.

MKKS p.Leu26Val

c.76C>G · rs774340585 · VCV2131327

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0931 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
AlphaMissense	0.0931	likely benign
REVEL	0.407	indeterminate
SaProt	LLR -8.12	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 2.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 8,264 bp · p 0.96 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,014 alleles

Overall 6.2e-05% 1/1,613,788 alleles · very rare exomes 1/1,461,436 · genomes 0/152,352 · 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: MKKS
Protein: p.Leu26Val
Coding: c.76C>G
MANE Select: NM_170784
dbSNP: rs774340585
Type: single nucleotide variant
Location: chr20:10413439 (GRCh38)
Gene constraint: LOEUF 1.112 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.05

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-leu26val (accessed [today's date]).

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