Is CCBE1 p.Arg301Gln (c.902G>A) pathogenic?

CCBE1 p.Arg301Gln (c.902G>A) is classified Uncertain significance in CCBE1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-05-08). AlphaMissense: likely benign (0.1576); Ultra-rare (popmax 0.0409%, nfe); Associated with CCBE1-related disorder.

What condition is associated with CCBE1 p.Arg301Gln (c.902G>A)?

CCBE1 p.Arg301Gln (c.902G>A) is associated with CCBE1-related disorder, Hennekam lymphangiectasia-lymphedema syndrome 1 (ClinVar).

How common is CCBE1 p.Arg301Gln (c.902G>A) in the general population?

CCBE1 p.Arg301Gln (c.902G>A) is ultra-rare (popmax 0.0409%, nfe) (gnomAD).

What do computational predictors say about CCBE1 p.Arg301Gln (c.902G>A)?

AlphaMissense predicts likely benign (score 0.1576) — an in-silico prediction, not a clinical call.

CCBE1 p.Arg301Gln

c.902G>A · rs200772179 · VCV890299

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1576 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0409%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CCBE1-related disorder

Computational evidence

Protein change
AlphaMissense	0.1576	likely benign
REVEL	0.145	moderately benign-leaning
SaProt	LLR -7.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 261 kb · p 0.54 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0409% European (non-Finnish) · 483/1,180,040 alleles

Filtering AF 0.0379% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0366%

Overall 0.0328% 530/1,614,232 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0409%	2,443
Remaining individualsnot grpmax-eligible	0.0368%	2,718
Admixed American	0.0183%	5,457
African / African-American	0.00933%	10,724
South Asian	0.00659%	15,181

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.Arg301Gln
Coding: c.902G>A
MANE Select: NM_133459
dbSNP: rs200772179
Type: single nucleotide variant
Location: chr18:59439690 (GRCh38)
Gene constraint: LOEUF 0.933 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.61
Residue 301: the collagen-like 2 domain; the 'disordered' region

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

Disease context

CCBE1-related disorder

Also linked: Hennekam lymphangiectasia-lymphedema syndrome 1

Similar variants

CCBE1 p.Arg301Trp Uncertain significance ★★ ⚠ same residue
CCBE1 p.Arg108Ter Pathogenic ★★ same condition
CCBE1 p.Arg118Ter Pathogenic/Likely 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

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-arg301gln (accessed [today's date]).

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