Is CCBE1 p.His186Arg (c.557A>G) pathogenic?

CCBE1 p.His186Arg (c.557A>G) is classified Benign/Likely benign in CCBE1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0628); Rare (popmax 0.405%, sas); Associated with Inborn genetic diseases.

What condition is associated with CCBE1 p.His186Arg (c.557A>G)?

CCBE1 p.His186Arg (c.557A>G) is associated with Inborn genetic diseases, Hennekam lymphangiectasia-lymphedema syndrome 1 (ClinVar).

How common is CCBE1 p.His186Arg (c.557A>G) in the general population?

CCBE1 p.His186Arg (c.557A>G) is rare (popmax 0.405%, sas) (gnomAD).

What do computational predictors say about CCBE1 p.His186Arg (c.557A>G)?

AlphaMissense predicts likely benign (score 0.0628) — an in-silico prediction, not a clinical call.

CCBE1 p.His186Arg

c.557A>G · rs115071386 · VCV890865

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0628 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.405%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0628	likely benign
REVEL	0.105	moderately benign-leaning
SaProt	LLR -5.42	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 0.073	GERP -0.89, phastCons 0.016
Regional constraint	o/e 1.03	unconstrained · MANE · 261 kb · p 0.54 · regional, not allelic
Overall
CADD	11.62	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.405% South Asian · 369/91,042 alleles

Filtering AF 0.371% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.358%

Overall 0.0542% 874/1,612,706 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.405%	247
Middle Eastern	0.165%	606
Ashkenazi Jewishnot grpmax-eligible	0.111%	897
Remaining individualsnot grpmax-eligible	0.0832%	1,201
Admixed American	0.0383%	2,610
European (non-Finnish)	0.0322%	3,102
African / African-American	0.008%	12,501
East Asian	0.00223%	44,880

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.His186Arg
Coding: c.557A>G
MANE Select: NM_133459
dbSNP: rs115071386
Type: single nucleotide variant
Location: chr18:59454948 (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.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
CCBE1 p.Ala96Gly Uncertain significance ★★ ⚠ same condition
CCBE1 p.Arg121Gln 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-his186arg (accessed [today's date]).

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