Is MKKS p.Arg23Ser (c.69G>C) pathogenic?

MKKS p.Arg23Ser (c.69G>C) is classified Uncertain significance in MKKS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-19). AlphaMissense: likely benign (0.158); Ultra-rare (popmax 0.0183%, amr); Associated with McKusick-Kaufman syndrome.

What condition is associated with MKKS p.Arg23Ser (c.69G>C)?

MKKS p.Arg23Ser (c.69G>C) is associated with McKusick-Kaufman syndrome, Bardet-Biedl syndrome (ClinVar).

How common is MKKS p.Arg23Ser (c.69G>C) in the general population?

MKKS p.Arg23Ser (c.69G>C) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

What do computational predictors say about MKKS p.Arg23Ser (c.69G>C)?

AlphaMissense predicts likely benign (score 0.158) — an in-silico prediction, not a clinical call.

MKKS p.Arg23Ser

c.69G>C · rs748670841 · VCV2146874

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.158 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

McKusick-Kaufman syndrome

Computational evidence

Protein change
AlphaMissense	0.158	likely benign
REVEL	0.199	benign-leaning
SaProt	LLR -7.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.5	GERP 1.3, phastCons 0.93
Regional constraint	o/e 1.00	unconstrained · MANE · 8,264 bp · p 0.96 · regional, not allelic
Overall
CADD	13.15	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 0.0183% Admixed American · 11/60,014 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.000805% 13/1,613,996 alleles · ultra-rare exomes 13/1,461,690 · genomes 0/152,306 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,456
Remaining individualsnot grpmax-eligible	0.0032%	31,250

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.Arg23Ser
Coding: c.69G>C
MANE Select: NM_170784
dbSNP: rs748670841
Type: single nucleotide variant
Location: chr20:10413446 (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

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

Also linked: Bardet-Biedl syndrome

Similar variants

MKKS p.Arg23Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-arg23ser (accessed [today's date]).

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