Is CCBE1 p.Arg108Ter (c.322C>T) pathogenic?

CCBE1 p.Arg108Ter (c.322C>T) is classified Pathogenic in CCBE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-02). Very rare (popmax 0.00401%, afr); Associated with Hennekam lymphangiectasia-lymphedema syndrome 1.

What condition is associated with CCBE1 p.Arg108Ter (c.322C>T)?

CCBE1 p.Arg108Ter (c.322C>T) is associated with Hennekam lymphangiectasia-lymphedema syndrome 1 (ClinVar).

How common is CCBE1 p.Arg108Ter (c.322C>T) in the general population?

CCBE1 p.Arg108Ter (c.322C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

CCBE1 p.Arg108Ter

c.322C>T · rs201954546 · VCV2994186

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Conditions

Hennekam lymphangiectasia-lymphedema syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 11
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 1.5, phastCons 1
Overall
CADD	48.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,902 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000558% 9/1,614,018 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,967
East Asian	0.00223%	44,902
European (non-Finnish)	0.000424%	236,006

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.Arg108Ter
Coding: c.322C>T
MANE Select: NM_133459
dbSNP: rs201954546
Type: single nucleotide variant
Location: chr18:59469551 (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 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
CCBE1 p.Arg127Gln Uncertain significance ★★ ⚠ same condition
CCBE1 p.Arg282Gln 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-arg108ter (accessed [today's date]).

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