Is CCBE1 p.Pro97Ser (c.289C>T) pathogenic?

CCBE1 p.Pro97Ser (c.289C>T) is classified Uncertain significance in CCBE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-24). AlphaMissense: ambiguous (0.4789); Very rare (popmax 0.00333%, amr).

How common is CCBE1 p.Pro97Ser (c.289C>T) in the general population?

CCBE1 p.Pro97Ser (c.289C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CCBE1 p.Pro97Ser (c.289C>T)?

AlphaMissense predicts ambiguous (score 0.4789) — an in-silico prediction, not a clinical call.

CCBE1 p.Pro97Ser

c.289C>T · rs1216440169 · VCV1404862

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4789 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Computational evidence

Protein change
AlphaMissense	0.4789	ambiguous
REVEL	0.62	indeterminate
SaProt	LLR -6.97	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 261 kb · p 0.54 · regional, not allelic
Overall
CADD	27.0	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 0.00333% Admixed American · 2/60,012 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000186% 3/1,614,028 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,006
European (non-Finnish)	8.47e-05%	1,180,050

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.Pro97Ser
Coding: c.289C>T
MANE Select: NM_133459
dbSNP: rs1216440169
Type: single nucleotide variant
Location: chr18:59469584 (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

Similar variants

CCBE1 p.Pro97Ala Uncertain significance ★ ⚠ same residue
CCBE1 p.Arg108Ter Pathogenic ★★ same type
CCBE1 p.Arg118Ter Pathogenic/Likely pathogenic ★★ same type
CCBE1 c.654+5G>C Uncertain significance ★★ same type
CCBE1 c.*203A>G Uncertain significance ★★ same type
CCBE1 c.*4173A>G Uncertain significance ★★ same type
CCBE1 p.Ala28Val Uncertain significance ★★ ⚠ same type
CCBE1 p.Ala322Val 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/ccbe1-p-pro97ser (accessed [today's date]).

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