Is CBY2 p.Val448Phe (c.1342G>T) pathogenic?

CBY2 p.Val448Phe (c.1342G>T) is classified Uncertain significance in CBY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-12). AlphaMissense: likely benign (0.2796); Ultra-rare (popmax 0.0107%, afr).

How common is CBY2 p.Val448Phe (c.1342G>T) in the general population?

CBY2 p.Val448Phe (c.1342G>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about CBY2 p.Val448Phe (c.1342G>T)?

AlphaMissense predicts likely benign (score 0.2796) — an in-silico prediction, not a clinical call.

CBY2 p.Val448Phe

c.1342G>T · rs777266583 · VCV3138093

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2796 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2796	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -7.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.29	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 2.8	GERP -1.1, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.035 · regional, not allelic
Overall
CADD	22.1	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 0.0107% African / African-American · 8/74,612 alleles

Filtering AF 0.0053% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00382%

Overall 0.001% 16/1,596,634 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,327
Admixed American	0.00514%	19,467
Remaining individualsnot grpmax-eligible	0.00487%	20,548
European (non-Finnish)	0.000171%	585,233

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: CBY2
Protein: p.Val448Phe
Coding: c.1342G>T
MANE Select: NM_152719
dbSNP: rs777266583
Type: single nucleotide variant
Location: chr13:45714367 (GRCh38)
Gene constraint: LOEUF 1.393 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 63.75

Full CBY2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CBY2 p.Ala163Thr Uncertain significance ★ ⚠ same type
CBY2 p.Ala205Asp Uncertain significance ★ ⚠ same type
CBY2 p.Ala214Thr Uncertain significance ★ ⚠ same type
CBY2 p.Ala214Val Uncertain significance ★ ⚠ same type
CBY2 p.Ala224Glu Uncertain significance ★ ⚠ same type
CBY2 p.Ala269Val Uncertain significance ★ ⚠ same type
CBY2 p.Ala76Thr Uncertain significance ★ ⚠ same type
CBY2 p.Arg141His 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/cby2-p-val448phe (accessed [today's date]).

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