Is CCBE1 p.Glu65= (c.195G>A) pathogenic?

CCBE1 p.Glu65= (c.195G>A) is classified Benign/Likely benign in CCBE1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-06-01). Rare (popmax 0.744%, nfe); Associated with Hennekam lymphangiectasia-lymphedema syndrome 1.

What condition is associated with CCBE1 p.Glu65= (c.195G>A)?

CCBE1 p.Glu65= (c.195G>A) is associated with Hennekam lymphangiectasia-lymphedema syndrome 1 (ClinVar).

How common is CCBE1 p.Glu65= (c.195G>A) in the general population?

CCBE1 p.Glu65= (c.195G>A) is rare (popmax 0.744%, nfe) (gnomAD).

CCBE1 p.Glu65=

c.195G>A · rs116673304 · VCV774935

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.744%, nfe)

Conditions

Hennekam lymphangiectasia-lymphedema syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.78, phastCons 1
Overall
CADD	19.65	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.744% European (non-Finnish) · 8,775/1,179,958 alleles

Filtering AF 0.731% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.725%

Overall 0.606% 9,783/1,614,044 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.744%	134
Admixed American	0.653%	153
Remaining individualsnot grpmax-eligible	0.539%	185
Finnishnot grpmax-eligible	0.248%	402
Amishnot grpmax-eligible	0.22%	455
Ashkenazi Jewishnot grpmax-eligible	0.122%	822
African / African-American	0.101%	988
Middle Eastern	0.0166%	6,030
South Asian	0.00549%	18,217

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.Glu65=
Coding: c.195G>A
MANE Select: NM_133459
dbSNP: rs116673304
Type: single nucleotide variant
Location: chr18:59696646 (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.Glu65Lys 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-glu65 (accessed [today's date]).

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