Is CCBE1 p.Pro87Gln (c.260C>A) pathogenic?

CCBE1 p.Pro87Gln (c.260C>A) is classified Conflicting classifications of pathogenicity in CCBE1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-25). AlphaMissense: ambiguous (0.4453); Ultra-rare (popmax 0.0996%, sas); Associated with Hennekam lymphangiectasia-lymphedema syndrome 1.

What condition is associated with CCBE1 p.Pro87Gln (c.260C>A)?

CCBE1 p.Pro87Gln (c.260C>A) is associated with Hennekam lymphangiectasia-lymphedema syndrome 1 (ClinVar).

How common is CCBE1 p.Pro87Gln (c.260C>A) in the general population?

CCBE1 p.Pro87Gln (c.260C>A) is ultra-rare (popmax 0.0996%, sas) (gnomAD).

What do computational predictors say about CCBE1 p.Pro87Gln (c.260C>A)?

AlphaMissense predicts ambiguous (score 0.4453) — an in-silico prediction, not a clinical call.

CCBE1 p.Pro87Gln

c.260C>A · rs756973760 · VCV625905

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4453 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0996%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Hennekam lymphangiectasia-lymphedema syndrome 1

Computational evidence

Protein change
AlphaMissense	0.4453	ambiguous
REVEL	0.726	pathogenic-leaning
SaProt	LLR -10.20	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 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 261 kb · p 0.54 · regional, not allelic
Overall
CADD	25.3	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 0.0996% South Asian · 90/90,334 alleles

Filtering AF 0.083% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0768%

Overall 0.00662% 105/1,585,546 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0996%	1,004
Middle Eastern	0.0167%	5,986
Remaining individualsnot grpmax-eligible	0.013%	7,686
East Asian	0.00449%	22,292
European (non-Finnish)	0.000346%	288,656

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.Pro87Gln
Coding: c.260C>A
MANE Select: NM_133459
dbSNP: rs756973760
Type: single nucleotide variant
Location: chr18:59480191 (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

Hennekam lymphangiectasia-lymphedema syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CCBE1 p.Pro87Ser Uncertain significance ★★ ⚠ same residue
CCBE1 p.Arg108Ter Pathogenic ★★ same condition
CCBE1 c.654+5G>C Uncertain significance ★★ same condition
CCBE1 c.*203A>G Uncertain significance ★★ same condition
CCBE1 c.*4173A>G Uncertain significance ★★ same condition
CCBE1 p.Ala28Val Uncertain significance ★★ ⚠ same condition
CCBE1 p.Ala96Gly Uncertain significance ★★ ⚠ same condition
CCBE1 p.Arg125Trp 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-pro87gln (accessed [today's date]).

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