Is CAMK2B p.Arg641Cys (c.1921C>T) pathogenic?

CAMK2B p.Arg641Cys (c.1921C>T) is classified Uncertain significance in CAMK2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-10). AlphaMissense: likely pathogenic (0.9747); Very rare (popmax 8.48e-05%, nfe); Associated with CAMK2B-related disorder.

What condition is associated with CAMK2B p.Arg641Cys (c.1921C>T)?

CAMK2B p.Arg641Cys (c.1921C>T) is associated with CAMK2B-related disorder (ClinVar).

How common is CAMK2B p.Arg641Cys (c.1921C>T) in the general population?

CAMK2B p.Arg641Cys (c.1921C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CAMK2B p.Arg641Cys (c.1921C>T)?

AlphaMissense predicts likely pathogenic (score 0.9747) — an in-silico prediction, not a clinical call.

CAMK2B p.Arg641Cys

c.1921C>T · rs2128857849 · VCV1676332

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9747 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CAMK2B-related disorder

Computational evidence

Protein change
AlphaMissense	0.9747	likely pathogenic
REVEL	0.518	indeterminate
SaProt	LLR -12.54	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 821 bp · p 1.5e-07 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.48e-05% European (non-Finnish) · 1/1,179,882 alleles

Overall 6.85e-05% 1/1,460,082 alleles · very rare

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.Arg641Cys
Coding: c.1921C>T
MANE Select: NM_001220
dbSNP: rs2128857849
Type: single nucleotide variant
Location: chr7:44220142 (GRCh38)
Gene constraint: LOEUF 0.45 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 72.35 · 4 PDB
Residue 641: a UniProt-annotated variant site (in mrd54); a β-strand

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

Disease context

CAMK2B-related disorder

Similar variants

CAMK2B p.Arg641= Benign/Likely benign ★★ same residue
CAMK2B p.Gln165Glu Uncertain significance ★★ ⚠ same condition
CAMK2B p.Ser447Tyr Uncertain significance ★★ ⚠ same condition
CAMK2B p.Asp19Asn Uncertain significance ★ ⚠ same condition
CAMK2B p.Ser447Phe Uncertain significance ⚠ same condition
CAMK2B p.Thr287_Glu289del Uncertain significance same condition
CAMK2B p.Val607fs Uncertain significance same condition
CAMK2B c.903+2T>C 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-arg641cys (accessed [today's date]).

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