Is CNBD2 p.Arg133Cys (c.397C>T) pathogenic?

CNBD2 p.Arg133Cys (c.397C>T) is classified Uncertain significance in CNBD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-24). AlphaMissense: likely benign (0.2291); Rare (popmax 0.117%, afr).

How common is CNBD2 p.Arg133Cys (c.397C>T) in the general population?

CNBD2 p.Arg133Cys (c.397C>T) is rare (popmax 0.117%, afr) (gnomAD).

What do computational predictors say about CNBD2 p.Arg133Cys (c.397C>T)?

AlphaMissense predicts likely benign (score 0.2291) — an in-silico prediction, not a clinical call.

CNBD2 p.Arg133Cys

c.397C>T · VCV4230660

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2291 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.117%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2291	likely benign
REVEL	0.55	indeterminate
SaProt	LLR -11.12	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 0.75, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 62 kb · p 0.4 · regional, not allelic
Overall
CADD	25.5	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 0.117% African / African-American · 88/75,036 alleles

Filtering AF 0.0975% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0901%

Overall 0.0101% 163/1,613,218 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.117%	853
East Asian	0.098%	1,020
Admixed American	0.0183%	5,456
Remaining individualsnot grpmax-eligible	0.00801%	12,486
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
Finnishnot grpmax-eligible	0.00156%	63,986
South Asian	0.0011%	91,022
European (non-Finnish)	0.00102%	98,329

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: CNBD2
Protein: p.Arg133Cys
Coding: c.397C>T
MANE Select: NM_001365709
Type: single nucleotide variant
Location: chr20:35980612 (GRCh38)
Gene constraint: LOEUF 1.173 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.79
Residue 133: a binding site

Full CNBD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNBD2 p.Arg133His Uncertain significance ★ ⚠ same residue
CNBD2 p.Ala121Thr Uncertain significance ★ ⚠ same type
CNBD2 p.Ala566Gly Uncertain significance ★ ⚠ same type
CNBD2 p.Ala566Thr Uncertain significance ★ ⚠ same type
CNBD2 p.Ala576Thr Uncertain significance ★ ⚠ same type
CNBD2 p.Ala88Thr Uncertain significance ★ ⚠ same type
CNBD2 p.Arg118Trp Uncertain significance ★ ⚠ same type
CNBD2 p.Arg139Cys 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/cnbd2-p-arg133cys (accessed [today's date]).

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