Is CBLL1 p.Pro223Leu (c.668C>T) pathogenic?

CBLL1 p.Pro223Leu (c.668C>T) is classified Uncertain significance in CBLL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: ambiguous (0.3752); Absent from gnomAD v4.1.

How common is CBLL1 p.Pro223Leu (c.668C>T) in the general population?

CBLL1 p.Pro223Leu (c.668C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBLL1 p.Pro223Leu (c.668C>T)?

AlphaMissense predicts ambiguous (score 0.3752) — an in-silico prediction, not a clinical call.

CBLL1 p.Pro223Leu

c.668C>T · VCV4219992

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3752 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3752	ambiguous
REVEL	0.179	moderately benign-leaning
SaProt	LLR -8.64	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 241 bp · p 0.85 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CBLL1
Protein: p.Pro223Leu
Coding: c.668C>T
MANE Select: NM_024814
Type: single nucleotide variant
Location: chr7:107758370 (GRCh38)
Gene constraint: LOEUF 0.251 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.68

Full CBLL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CBLL1 p.Ala38Val Uncertain significance ★ ⚠ same type
CBLL1 p.Ala418Val Uncertain significance ★ ⚠ same type
CBLL1 p.Ala41Pro Uncertain significance ★ ⚠ same type
CBLL1 p.Ala41Val Uncertain significance ★ ⚠ same type
CBLL1 p.Arg24Lys Uncertain significance ★ ⚠ same type
CBLL1 p.Arg261His Uncertain significance ★ ⚠ same type
CBLL1 p.Arg46Gly Uncertain significance ★ ⚠ same type
CBLL1 p.Arg487Lys 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/cbll1-p-pro223leu (accessed [today's date]).

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