Is CACNB2 p.Arg70Cys (c.208C>T) pathogenic?

CACNB2 p.Arg70Cys (c.208C>T) is classified Uncertain significance in CACNB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-28). AlphaMissense: likely pathogenic (0.973); Very rare (popmax 0.00445%, sas); Associated with autism spectrum disorder.

What condition is associated with CACNB2 p.Arg70Cys (c.208C>T)?

CACNB2 p.Arg70Cys (c.208C>T) is associated with autism spectrum disorder (ClinVar).

How common is CACNB2 p.Arg70Cys (c.208C>T) in the general population?

CACNB2 p.Arg70Cys (c.208C>T) is very rare (popmax 0.00445%, sas) (gnomAD).

What do computational predictors say about CACNB2 p.Arg70Cys (c.208C>T)?

AlphaMissense predicts likely pathogenic (score 0.973) — an in-silico prediction, not a clinical call.

CACNB2 p.Arg70Cys

c.208C>T · rs760538597 · VCV545669

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.973 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autism spectrum disorder

Computational evidence

Protein change
AlphaMissense	0.973	likely pathogenic
REVEL	0.543	indeterminate
SaProt	LLR -8.21	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 399 kb · p 0.0029 · regional, not allelic
Overall
CADD	33.0	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 0.00445% South Asian · 4/89,958 alleles

Filtering AF 0.00144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00186% 29/1,562,280 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00445%	22,489
African / African-American	0.0042%	23,787
East Asian	0.00242%	41,334
Finnishnot grpmax-eligible	0.0017%	58,682
Remaining individualsnot grpmax-eligible	0.00167%	60,038
European (non-Finnish)	0.00165%	60,426

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: CACNB2
Protein: p.Arg70Cys
Coding: c.208C>T
MANE Select: NM_201596
dbSNP: rs760538597
Type: single nucleotide variant
Location: chr10:18150970 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.78 · 3 PDB
Residue 70: the 'disordered' region

Full CACNB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autism spectrum disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CACNB2 p.Arg70His Likely benign ★★ ⚠ same residue
CACNB2 c.1206+5G>A Uncertain significance ★★ same type
CACNB2 c.1303-3C>T Uncertain significance ★★ same type
CACNB2 c.1488+6G>A Uncertain significance ★★ same type
CACNB2 p.Ala105Thr Uncertain significance ★★ ⚠ same type
CACNB2 p.Ala118Val Uncertain significance ★★ ⚠ same type
CACNB2 p.Ala128Val Uncertain significance ★★ ⚠ same type
CACNB2 p.Ala139Ser 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/cacnb2-p-arg70cys (accessed [today's date]).

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