Is CNBD2 p.Arg215Trp (c.643C>T) pathogenic?

CNBD2 p.Arg215Trp (c.643C>T) is classified Uncertain significance in CNBD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). AlphaMissense: likely benign (0.1759); Ultra-rare (popmax 0.0231%, nfe).

How common is CNBD2 p.Arg215Trp (c.643C>T) in the general population?

CNBD2 p.Arg215Trp (c.643C>T) is ultra-rare (popmax 0.0231%, nfe) (gnomAD).

What do computational predictors say about CNBD2 p.Arg215Trp (c.643C>T)?

AlphaMissense predicts likely benign (score 0.1759) — an in-silico prediction, not a clinical call.

CNBD2 p.Arg215Trp

c.643C>T · rs147553424 · VCV2394123

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1759 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0231%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1759	likely benign
REVEL	0.505	indeterminate
SaProt	LLR -11.90	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 0.68	GERP -3.6, phastCons 0.99
Regional constraint	o/e 0.97	unconstrained · MANE · 62 kb · p 0.4 · regional, not allelic
Overall
CADD	21.0	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 0.0231% European (non-Finnish) · 272/1,180,006 alleles

Filtering AF 0.0208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0199%

Overall 0.018% 290/1,614,014 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0231%	4,338
Remaining individualsnot grpmax-eligible	0.0176%	5,681
African / African-American	0.00534%	18,726
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
East Asian	0.00223%	44,902
South Asian	0.0011%	91,076

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.Arg215Trp
Coding: c.643C>T
MANE Select: NM_001365709
dbSNP: rs147553424
Type: single nucleotide variant
Location: chr20:35984705 (GRCh38)
Gene constraint: LOEUF 1.173 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.79
Residue 215: a binding site

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

Similar variants

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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.Arg133Cys Uncertain significance ★ ⚠ same type
CNBD2 p.Arg133His 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-arg215trp (accessed [today's date]).

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