Is CBY3 p.Ala216Pro (c.646G>C) pathogenic?

CBY3 p.Ala216Pro (c.646G>C) is classified Uncertain significance in CBY3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.1117); Ultra-rare (popmax 0.0118%, amr).

How common is CBY3 p.Ala216Pro (c.646G>C) in the general population?

CBY3 p.Ala216Pro (c.646G>C) is ultra-rare (popmax 0.0118%, amr) (gnomAD).

What do computational predictors say about CBY3 p.Ala216Pro (c.646G>C)?

AlphaMissense predicts likely benign (score 0.1117) — an in-silico prediction, not a clinical call.

CBY3 p.Ala216Pro

c.646G>C · VCV4220114

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1117 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0118%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1117	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -5.98	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -1.4	GERP -2
Regional constraint	o/e 1.19	unconstrained · MANE · 2,332 bp · p 0.00053 · regional, not allelic
Overall
CADD	15.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0118% Admixed American · 6/50,908 alleles

Filtering AF 0.00512% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00347%

Overall 0.000391% 6/1,535,398 alleles · ultra-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: CBY3
Protein: p.Ala216Pro
Coding: c.646G>C
MANE Select: NM_001746 · reported on NM_001164444
Type: single nucleotide variant
Location: chr5:179678666 (GRCh38)

Full CBY3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/cby3-p-ala216pro (accessed [today's date]).

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