Is CBY3 p.Thr141Pro (c.421A>C) pathogenic?

CBY3 p.Thr141Pro (c.421A>C) is classified Uncertain significance in CBY3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). AlphaMissense: likely benign (0.0915); Very rare (popmax 0.00436%, nfe).

How common is CBY3 p.Thr141Pro (c.421A>C) in the general population?

CBY3 p.Thr141Pro (c.421A>C) is very rare (popmax 0.00436%, nfe) (gnomAD).

What do computational predictors say about CBY3 p.Thr141Pro (c.421A>C)?

AlphaMissense predicts likely benign (score 0.0915) — an in-silico prediction, not a clinical call.

CBY3 p.Thr141Pro

c.421A>C · rs1478142430 · VCV2310584

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0915 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00436%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0915	likely benign
REVEL	0.002	strongly benign-leaning
SaProt	LLR -4.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -3.6	GERP -3.4
Regional constraint	o/e 1.19	unconstrained · MANE · 2,332 bp · p 0.00053 · regional, not allelic
Overall
CADD	5.01	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 0.00436% European (non-Finnish) · 50/1,145,930 alleles

Filtering AF 0.00336% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00303%

Overall 0.00339% 52/1,535,302 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00436%	22,919
South Asian	0.00238%	41,978

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.Thr141Pro
Coding: c.421A>C
MANE Select: NM_001746 · reported on NM_001164444
dbSNP: rs1478142430
Type: single nucleotide variant
Location: chr5:179678891 (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-thr141pro (accessed [today's date]).

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