Is CBS p.Glu270Lys (c.808G>A) pathogenic?

CBS p.Glu270Lys (c.808G>A) is classified Uncertain significance in CBS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-02). AlphaMissense: ambiguous (0.4446); Very rare (popmax 0.00469%, eas); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with CBS p.Glu270Lys (c.808G>A)?

CBS p.Glu270Lys (c.808G>A) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is CBS p.Glu270Lys (c.808G>A) in the general population?

CBS p.Glu270Lys (c.808G>A) is very rare (popmax 0.00469%, eas) (gnomAD).

What do computational predictors say about CBS p.Glu270Lys (c.808G>A)?

AlphaMissense predicts ambiguous (score 0.4446) — an in-silico prediction, not a clinical call.

CBS p.Glu270Lys

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.808G>A · rs1337180584 · VCV2166885

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4446 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00469%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.4446	ambiguous
REVEL	0.783	moderately pathogenic-leaning
SaProt	LLR -11.93	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.1, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 11 kb · p 6.7e-07 · regional, not allelic
Overall
CADD	29.2	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 0.00469% East Asian · 1/21,306 alleles

Overall 0.000531% 1/188,268 alleles · very rare

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: CBS
Protein: p.Glu270Lys
Coding: c.808G>A
MANE Select: NM_000071
dbSNP: rs1337180584
Type: single nucleotide variant
Location: chr21:43063920 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 270: an α-helix; a UniProt-annotated variant site (in cbsd)

Full CBS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

CBS c.1224-2A>C Pathogenic ★★ same condition
CBS c.954+1G>A Pathogenic/Likely pathogenic ★★ same condition
CBS p.Ala114Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
CBS p.Ala288Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
CBS p.Ala331Glu Pathogenic/Likely pathogenic ★★ same condition
CBS p.Arg121His Pathogenic/Likely pathogenic ★★ same condition
CBS p.Arg125Gln Pathogenic ★★ ⚠ same condition
CBS p.Arg266Lys Pathogenic/Likely pathogenic ★★ ⚠ 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/cbs-p-glu270lys (accessed [today's date]).

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