Is CBY2 p.Val49Ala (c.146T>C) pathogenic?

CBY2 p.Val49Ala (c.146T>C) is classified Uncertain significance in CBY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely benign (0.2401); Absent from gnomAD v4.1.

How common is CBY2 p.Val49Ala (c.146T>C) in the general population?

CBY2 p.Val49Ala (c.146T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBY2 p.Val49Ala (c.146T>C)?

AlphaMissense predicts likely benign (score 0.2401) — an in-silico prediction, not a clinical call.

CBY2 p.Val49Ala

c.146T>C · VCV4648831

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2401 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,612,564)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2401	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -5.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.9	GERP 1.2, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 12 kb · p 0.035 · regional, not allelic
Overall
CADD	19.73	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

No allele count reported in gnomAD v4.1 (AN 1,612,564). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CBY2
Protein: p.Val49Ala
Coding: c.146T>C
MANE Select: NM_152719
Type: single nucleotide variant
Location: chr13:45702845 (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-val49ala (accessed [today's date]).

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