Is CAMK2B p.Ser490Pro (c.1468T>C) pathogenic?

CAMK2B p.Ser490Pro (c.1468T>C) is classified Uncertain significance in CAMK2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-30). AlphaMissense: likely benign (0.0666); Ultra-rare (popmax 0.0197%, mid).

How common is CAMK2B p.Ser490Pro (c.1468T>C) in the general population?

CAMK2B p.Ser490Pro (c.1468T>C) is ultra-rare (popmax 0.0197%, mid) (gnomAD).

What do computational predictors say about CAMK2B p.Ser490Pro (c.1468T>C)?

AlphaMissense predicts likely benign (score 0.0666) — an in-silico prediction, not a clinical call.

CAMK2B p.Ser490Pro

c.1468T>C · VCV4740832

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0666 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0197%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0666	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -10.96	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.8	GERP 1.8, phastCons 0.99
Regional constraint	o/e 1.05	unconstrained · MANE · 19 kb · p 0.35 · regional, not allelic
Overall
CADD	20.1	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

Grpmax group 0.0197% Middle Eastern · 1/5,080 alleles

Filtering AF 7.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.000301% 4/1,330,538 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0197%	5,080
European (non-Finnish)	0.000268%	373,108

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: CAMK2B
Protein: p.Ser490Pro
Coding: c.1468T>C
MANE Select: NM_001220
Type: single nucleotide variant
Location: chr7:44228796 (GRCh38)
Gene constraint: LOEUF 0.45 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 72.35 · 4 PDB
Residue 490: a UniProt-annotated variant site (in mrd54); the 'disordered' region

Full CAMK2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAMK2B p.Ser490Ala Uncertain significance ★ ⚠ same residue
CAMK2B p.Ser490Cys Uncertain significance ★ ⚠ same residue
CAMK2B c.903+2T>C Likely pathogenic ★★ same type
CAMK2B p.Arg29Ter Pathogenic/Likely pathogenic ★★ same type
CAMK2B p.Glu110Lys Pathogenic ★★ same type
CAMK2B p.Glu237Lys Pathogenic ★★ same type
CAMK2B p.Lys301Glu Pathogenic/Likely pathogenic ★★ same type
CAMK2B p.Pro139Leu Pathogenic/Likely pathogenic ★★ 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/camk2b-p-ser490pro (accessed [today's date]).

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