Is CCBE1 p.Leu222Pro (c.665T>C) pathogenic?

CCBE1 p.Leu222Pro (c.665T>C) is classified Uncertain significance in CCBE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-11). AlphaMissense: ambiguous (0.5434); Very rare (popmax 0.00667%, amr); Associated with Inborn genetic diseases.

What condition is associated with CCBE1 p.Leu222Pro (c.665T>C)?

CCBE1 p.Leu222Pro (c.665T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CCBE1 p.Leu222Pro (c.665T>C) in the general population?

CCBE1 p.Leu222Pro (c.665T>C) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about CCBE1 p.Leu222Pro (c.665T>C)?

AlphaMissense predicts ambiguous (score 0.5434) — an in-silico prediction, not a clinical call.

CCBE1 p.Leu222Pro

c.665T>C · rs1910767909 · VCV1980999

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5434 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5434	ambiguous
REVEL	0.652	pathogenic-leaning
SaProt	LLR -13.51	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 261 kb · p 0.54 · regional, not allelic
Overall
CADD	26.5	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

Grpmax group 0.00667% Admixed American · 4/59,946 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00263% 4/151,926 alleles · very rare

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: CCBE1
Protein: p.Leu222Pro
Coding: c.665T>C
MANE Select: NM_133459
dbSNP: rs1910767909
Type: single nucleotide variant
Location: chr18:59448093 (GRCh38)
Gene constraint: LOEUF 0.933 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.61

Full CCBE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CCBE1 p.Leu222Phe Uncertain significance ★★ ⚠ same residue
CCBE1 p.Ala28Val Uncertain significance ★★ ⚠ same condition
CCBE1 p.Ala322Val Uncertain significance ★★ ⚠ same condition
CCBE1 p.Arg121Gln Uncertain significance ★★ ⚠ same condition
CCBE1 p.Arg127Gln Uncertain significance ★★ ⚠ same condition
CCBE1 p.Arg162Gln Uncertain significance ★★ ⚠ same condition
CCBE1 p.Arg162Trp Uncertain significance ★★ ⚠ same condition
CCBE1 p.Arg301Trp Uncertain significance ★★ ⚠ same condition

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/ccbe1-p-leu222pro (accessed [today's date]).

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