Is CCBE1 p.Lys355Thr (c.1064A>C) pathogenic?

CCBE1 p.Lys355Thr (c.1064A>C) is classified Conflicting classifications of pathogenicity in CCBE1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.199); Rare (popmax 0.241%, nfe); Associated with Hennekam lymphangiectasia-lymphedema syndrome 1.

What condition is associated with CCBE1 p.Lys355Thr (c.1064A>C)?

CCBE1 p.Lys355Thr (c.1064A>C) is associated with Hennekam lymphangiectasia-lymphedema syndrome 1 (ClinVar).

How common is CCBE1 p.Lys355Thr (c.1064A>C) in the general population?

CCBE1 p.Lys355Thr (c.1064A>C) is rare (popmax 0.241%, nfe) (gnomAD).

What do computational predictors say about CCBE1 p.Lys355Thr (c.1064A>C)?

AlphaMissense predicts likely benign (score 0.199) — an in-silico prediction, not a clinical call.

CCBE1 p.Lys355Thr

c.1064A>C · rs139059968 · VCV888597

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.199 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.241%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hennekam lymphangiectasia-lymphedema syndrome 1

Computational evidence

Protein change
AlphaMissense	0.199	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -8.55	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 5	GERP 2.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 261 kb · p 0.54 · regional, not allelic
Overall
CADD	23.6	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 0.241% European (non-Finnish) · 2,838/1,180,018 alleles

Filtering AF 0.233% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.23%

Overall 0.192% 3,103/1,614,148 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.241%	416
Remaining individualsnot grpmax-eligible	0.2%	500
Admixed American	0.16%	625
African / African-American	0.0546%	1,830
Middle Eastern	0.0165%	6,060
Finnishnot grpmax-eligible	0.00312%	32,021

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.Lys355Thr
Coding: c.1064A>C
MANE Select: NM_133459
dbSNP: rs139059968
Type: single nucleotide variant
Location: chr18:59436065 (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.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
CCBE1 p.Arg127Gln 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-lys355thr (accessed [today's date]).

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