Is CKS2 p.Arg45Ser (c.135A>C) pathogenic?

CKS2 p.Arg45Ser (c.135A>C) is classified Uncertain significance in CKS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-14). AlphaMissense: likely benign (0.2669); Very rare (popmax 0.00212%, nfe).

How common is CKS2 p.Arg45Ser (c.135A>C) in the general population?

CKS2 p.Arg45Ser (c.135A>C) is very rare (popmax 0.00212%, nfe) (gnomAD).

What do computational predictors say about CKS2 p.Arg45Ser (c.135A>C)?

AlphaMissense predicts likely benign (score 0.2669) — an in-silico prediction, not a clinical call.

CKS2 p.Arg45Ser

c.135A>C · rs377258080 · VCV2594457

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2669 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2669	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -4.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 5,129 bp · p 0.016 · regional, not allelic
Overall
CADD	19.68	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 0.00212% European (non-Finnish) · 25/1,178,860 alleles

Filtering AF 0.00146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00155% 25/1,611,906 alleles · very rare exomes 20/1,459,752 · genomes 5/152,154 · 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: CKS2
Protein: p.Arg45Ser
Coding: c.135A>C
MANE Select: NM_001827
dbSNP: rs377258080
Type: single nucleotide variant
Location: chr9:89315245 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI 0.55 (gnomAD)
Structure: AlphaFold pLDDT 92.83 · 11 PDB
Residue 45: an α-helix

Full CKS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CKS2 p.Glu40Lys Uncertain significance ★ ⚠ same type
CKS2 p.His16Tyr Uncertain significance ★ ⚠ same type
CKS2 p.His21Tyr Uncertain significance ★ ⚠ same type
CKS2 p.Val32Ala Uncertain significance ★ ⚠ same type

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/cks2-p-arg45ser (accessed [today's date]).

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