Is CBS p.Cys272Ter (c.816T>A) pathogenic?

CBS p.Cys272Ter (c.816T>A) is classified Pathogenic/Likely pathogenic in CBS (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-06-15). Very rare (popmax 0.00208%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is CBS p.Cys272Ter (c.816T>A) in the general population?

CBS p.Cys272Ter (c.816T>A) is very rare (popmax 0.00208%, nfe) (gnomAD).

CBS p.Cys272Ter

Q: What condition is associated with CBS p.Cys272Ter (c.816T>A)?

CBS p.Cys272Ter (c.816T>A) is associated with familial thoracic aortic aneurysm and aortic dissection, homocystinuria, classic homocystinuria (ClinVar).

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.816T>A · rs528689432 · VCV439461

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00208%, nfe)

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 17
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.082	GERP -2.2, phastCons 0.044
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00208% European (non-Finnish) · 2/96,144 alleles

Filtering AF 0.000345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000129%

Overall 0.00112% 2/179,052 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.Cys272Ter
Coding: c.816T>A
MANE Select: NM_000071
dbSNP: rs528689432
Type: single nucleotide variant
Location: chr21:43063912 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 272: a β-strand

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

Also linked: homocystinuria classic homocystinuria

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

CBS p.Cys272= Likely benign ★ same residue
CBS c.1145+1G>A Pathogenic/Likely pathogenic ★★ same condition
CBS c.1223+1G>T Pathogenic ★★ same condition
CBS c.1224-2A>C Pathogenic ★★ same condition
CBS c.1358+1G>A Pathogenic ★★ same condition
CBS c.1359-1G>C Pathogenic/Likely pathogenic ★★ same condition
CBS c.1468-1G>A Likely pathogenic ★★ same condition
CBS c.1552+1G>A 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-cys272ter (accessed [today's date]).

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