Is CBS p.Ala226Asp (c.677C>A) pathogenic?

CBS p.Ala226Asp (c.677C>A) is classified Conflicting classifications of pathogenicity in CBS (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-04-07). AlphaMissense: likely benign (0.3171); Very rare (popmax 0.000197%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with CBS p.Ala226Asp (c.677C>A)?

CBS p.Ala226Asp (c.677C>A) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is CBS p.Ala226Asp (c.677C>A) in the general population?

CBS p.Ala226Asp (c.677C>A) is very rare (popmax 0.000197%, nfe) (gnomAD).

What do computational predictors say about CBS p.Ala226Asp (c.677C>A)?

AlphaMissense predicts likely benign (score 0.3171) — an in-silico prediction, not a clinical call.

CBS p.Ala226Asp

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.677C>A · rs2517443210 · VCV2781936

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.3171 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000197%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.3171	likely benign
REVEL	0.539	indeterminate
SaProt	LLR -8.08	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 0.17, phastCons 1
Regional constraint	o/e 0.24	constrained · MANE · 1,046 bp · p 7.5e-10 · regional, not allelic
Overall
CADD	22.5	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 0.000197% European (non-Finnish) · 2/1,013,602 alleles

Filtering AF 3.3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.2e-05%

Overall 0.000156% 2/1,283,840 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.Ala226Asp
Coding: c.677C>A
MANE Select: NM_000071
dbSNP: rs2517443210
Type: single nucleotide variant
Location: chr21:43065262 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 226: a UniProt-annotated variant site (in cbsd; presents 20% of the wild-type activity; dramatically reduced capacity to form multimeric quaternary structure)

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 p.Ala226Thr Pathogenic/Likely pathogenic ★★ ⚠ same residue
CBS p.Ala226Pro Uncertain significance ★★ ⚠ same residue
CBS p.Ala226Ser Likely pathogenic ★ ⚠ same residue
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

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-ala226asp (accessed [today's date]).

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