Is CBY3 p.Ala216Val (c.647C>T) pathogenic?

CBY3 p.Ala216Val (c.647C>T) is classified Uncertain significance in CBY3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-28). AlphaMissense: likely benign (0.1224); Ultra-rare (popmax 0.0167%, mid).

How common is CBY3 p.Ala216Val (c.647C>T) in the general population?

CBY3 p.Ala216Val (c.647C>T) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about CBY3 p.Ala216Val (c.647C>T)?

AlphaMissense predicts likely benign (score 0.1224) — an in-silico prediction, not a clinical call.

CBY3 p.Ala216Val

c.647C>T · VCV4648833

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1224 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1224	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -7.19	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.1	GERP -2.1, phastCons 0.023
Regional constraint	o/e 1.19	unconstrained · MANE · 2,332 bp · p 0.00053 · regional, not allelic
Overall
CADD	16.9	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 0.0167% Middle Eastern · 1/6,006 alleles

Filtering AF 0.0054% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00389%

Overall 0.000977% 15/1,535,408 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	6,006
African / African-American	0.011%	9,123
South Asian	0.00595%	16,803
Remaining individualsnot grpmax-eligible	0.00167%	59,902

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.Ala216Val
Coding: c.647C>T
MANE Select: NM_001746 · reported on NM_001164444
Type: single nucleotide variant
Location: chr5:179678665 (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-ala216val (accessed [today's date]).

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