Is CCBE1 p.Pro287Ser (c.859C>T) pathogenic?

CCBE1 p.Pro287Ser (c.859C>T) is classified Uncertain significance in CCBE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-20). AlphaMissense: ambiguous (0.3573); Very rare (popmax 0.000593%, nfe).

How common is CCBE1 p.Pro287Ser (c.859C>T) in the general population?

CCBE1 p.Pro287Ser (c.859C>T) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about CCBE1 p.Pro287Ser (c.859C>T)?

AlphaMissense predicts ambiguous (score 0.3573) — an in-silico prediction, not a clinical call.

CCBE1 p.Pro287Ser

c.859C>T · rs749999713 · VCV1958621

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3573 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3573	ambiguous
REVEL	0.663	pathogenic-leaning
SaProt	LLR -9.61	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 261 kb · p 0.54 · regional, not allelic
Overall
CADD	25.8	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 0.000593% European (non-Finnish) · 7/1,180,034 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000547% 8/1,461,886 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)grpmax	0.000593%	168,576

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro287Ser
Coding: c.859C>T
MANE Select: NM_133459
dbSNP: rs749999713
Type: single nucleotide variant
Location: chr18:59439733 (GRCh38)
Gene constraint: LOEUF 0.933 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.61
Residue 287: the collagen-like 1 domain; the 'disordered' region

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

Similar variants

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
CCBE1 p.Ala96Gly 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-pro287ser (accessed [today's date]).

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