Is MKKS p.Val142Ala (c.425T>C) pathogenic?

MKKS p.Val142Ala (c.425T>C) is classified Uncertain significance in MKKS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-25). AlphaMissense: likely benign (0.2538); Very rare (popmax 8.47e-05%, nfe); Associated with Bardet-Biedl syndrome.

What condition is associated with MKKS p.Val142Ala (c.425T>C)?

MKKS p.Val142Ala (c.425T>C) is associated with Bardet-Biedl syndrome, McKusick-Kaufman syndrome (ClinVar).

How common is MKKS p.Val142Ala (c.425T>C) in the general population?

MKKS p.Val142Ala (c.425T>C) is very rare (popmax 8.47e-05%, nfe) (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.Val142Ala (c.425T>C)?

AlphaMissense predicts likely benign (score 0.2538) — an in-silico prediction, not a clinical call.

MKKS p.Val142Ala

c.425T>C · rs863224773 · VCV216705

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2538 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
AlphaMissense	0.2538	likely benign
REVEL	0.632	indeterminate
SaProt	LLR -9.22	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 9.3	GERP 2.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 8,264 bp · p 0.96 · regional, not allelic
Overall
CADD	24.3	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 8.47e-05% European (non-Finnish) · 1/1,180,018 alleles

Overall 6.2e-05% 1/1,614,020 alleles · very rare exomes 1/1,461,720 · genomes 0/152,300 · 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.Val142Ala
Coding: c.425T>C
MANE Select: NM_170784
dbSNP: rs863224773
Type: single nucleotide variant
Location: chr20:10413090 (GRCh38)
Gene constraint: LOEUF 1.112 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.05
Residue 142: 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-val142ala (accessed [today's date]).

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