Is CCBE1 p.Arg127Gln (c.380G>A) pathogenic?

CCBE1 p.Arg127Gln (c.380G>A) is classified Uncertain significance in CCBE1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-12-09). AlphaMissense: likely benign (0.112); Rare (popmax 0.107%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CCBE1 p.Arg127Gln (c.380G>A)?

CCBE1 p.Arg127Gln (c.380G>A) is associated with Inborn genetic diseases, Hennekam lymphangiectasia-lymphedema syndrome 1 (ClinVar).

How common is CCBE1 p.Arg127Gln (c.380G>A) in the general population?

CCBE1 p.Arg127Gln (c.380G>A) is rare (popmax 0.107%, nfe) (gnomAD).

What do computational predictors say about CCBE1 p.Arg127Gln (c.380G>A)?

AlphaMissense predicts likely benign (score 0.112) — an in-silico prediction, not a clinical call.

CCBE1 p.Arg127Gln

c.380G>A · rs141638717 · VCV892099

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.112 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.107%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.112	likely benign
REVEL	0.243	benign-leaning
SaProt	LLR -5.54	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 3.9	GERP -0.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 261 kb · p 0.54 · regional, not allelic
Overall
CADD	24.7	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 0.107% European (non-Finnish) · 1,264/1,180,036 alleles

Filtering AF 0.102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.1%

Overall 0.0827% 1,335/1,614,220 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.107%	934
Admixed American	0.0533%	1,876
Remaining individualsnot grpmax-eligible	0.032%	3,125
African / African-American	0.0186%	5,362
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
South Asian	0.00329%	30,363
Finnishnot grpmax-eligible	0.00156%	64,044

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.Arg127Gln
Coding: c.380G>A
MANE Select: NM_133459
dbSNP: rs141638717
Type: single nucleotide variant
Location: chr18:59469493 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Hennekam lymphangiectasia-lymphedema syndrome 1

Similar variants

CCBE1 p.Arg127Trp Uncertain significance ★★ ⚠ same residue
CCBE1 p.Arg127= Likely benign ★ 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.Ala322Val 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-arg127gln (accessed [today's date]).

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