Is CCBE1 p.Arg346Cys (c.1036C>T) pathogenic?

CCBE1 p.Arg346Cys (c.1036C>T) is classified Uncertain significance in CCBE1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-04). AlphaMissense: likely pathogenic (0.8741); Ultra-rare (popmax 0.0164%, mid); Associated with Hennekam lymphangiectasia-lymphedema syndrome 1.

What condition is associated with CCBE1 p.Arg346Cys (c.1036C>T)?

CCBE1 p.Arg346Cys (c.1036C>T) is associated with Hennekam lymphangiectasia-lymphedema syndrome 1 (ClinVar).

How common is CCBE1 p.Arg346Cys (c.1036C>T) in the general population?

CCBE1 p.Arg346Cys (c.1036C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CCBE1 p.Arg346Cys (c.1036C>T)?

AlphaMissense predicts likely pathogenic (score 0.8741) — an in-silico prediction, not a clinical call.

CCBE1 p.Arg346Cys

c.1036C>T · rs761881641 · VCV888599

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8741 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hennekam lymphangiectasia-lymphedema syndrome 1

Computational evidence

Protein change
AlphaMissense	0.8741	likely pathogenic
REVEL	0.778	moderately pathogenic-leaning
SaProt	LLR -15.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 1.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 261 kb · p 0.54 · regional, not allelic
Overall
CADD	29.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00462% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00422%

Overall 0.00471% 76/1,614,082 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
East Asian	0.00668%	14,965
European (non-Finnish)	0.00576%	17,354
South Asian	0.0022%	45,541
Admixed American	0.00167%	60,008
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Arg346Cys
Coding: c.1036C>T
MANE Select: NM_133459
dbSNP: rs761881641
Type: single nucleotide variant
Location: chr18:59436093 (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.Arg346Leu Uncertain significance ★★ ⚠ same residue
CCBE1 p.Arg346His 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

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-arg346cys (accessed [today's date]).

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