Is CBS p.Asp221= (c.663C>T) pathogenic?

CBS p.Asp221= (c.663C>T) is classified Likely benign in CBS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-20). Ultra-rare (popmax 0.0213%, eas); Associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED.

What condition is associated with CBS p.Asp221= (c.663C>T)?

CBS p.Asp221= (c.663C>T) is associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is CBS p.Asp221= (c.663C>T) in the general population?

CBS p.Asp221= (c.663C>T) is ultra-rare (popmax 0.0213%, eas) (gnomAD).

CBS p.Asp221=

c.663C>T · rs753964840 · VCV1129871

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0213%, eas)

Conditions

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -0.96, phastCons 1
Overall
CADD	9.905	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0213% East Asian · 7/32,816 alleles

Filtering AF 0.00992% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00706%

Overall 0.00371% 17/458,684 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0213%	4,688
South Asian	0.0171%	5,836

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.Asp221=
Coding: c.663C>T
MANE Select: NM_000071
dbSNP: rs753964840
Type: single nucleotide variant
Location: chr21:43065390 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB

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

Disease context

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial thoracic aortic aneurysm and aortic dissection

Similar variants

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.1552+1G>A Pathogenic/Likely pathogenic ★★ same condition
CBS c.451+1G>T Likely pathogenic ★★ same condition
CBS c.531+1G>A Likely pathogenic ★★ same condition
CBS c.736+2T>G Pathogenic ★★ same condition
CBS c.954+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-asp221 (accessed [today's date]).

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