Is CBS p.Arg132Ser (c.394C>A) pathogenic?

CBS p.Arg132Ser (c.394C>A) is classified Uncertain significance in CBS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-24). AlphaMissense: likely benign (0.2747); Ultra-rare (popmax 0.0125%, afr); Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is CBS p.Arg132Ser (c.394C>A) in the general population?

CBS p.Arg132Ser (c.394C>A) is ultra-rare (popmax 0.0125%, afr) (gnomAD).

What do computational predictors say about CBS p.Arg132Ser (c.394C>A)?

AlphaMissense predicts likely benign (score 0.2747) — an in-silico prediction, not a clinical call.

CBS p.Arg132Ser

Q: What condition is associated with CBS p.Arg132Ser (c.394C>A)?

CBS p.Arg132Ser (c.394C>A) is associated with familial thoracic aortic aneurysm and aortic dissection, 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.394C>A · rs140002610 · VCV263891

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2747 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0125%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.2747	likely benign
REVEL	0.585	indeterminate
SaProt	LLR -10.18	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.2, phastCons 1
Regional constraint	o/e 0.24	constrained · MANE · 1,046 bp · p 7.5e-10 · regional, not allelic
Overall
CADD	21.0	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 0.0125% African / African-American · 4/32,000 alleles

Filtering AF 0.00421% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00256%

Overall 0.000479% 5/1,044,314 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0125%	8,000
European (non-Finnish)	0.000137%	727,754

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.Arg132Ser
Coding: c.394C>A
MANE Select: NM_000071
dbSNP: rs140002610
Type: single nucleotide variant
Location: chr21:43066300 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 132: an α-helix

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: classic homocystinuria

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

CBS p.Arg132His Uncertain significance ★★ ⚠ same residue
CBS p.Arg132= Likely benign ★★ same residue
CBS p.Arg132Cys Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg132ser (accessed [today's date]).

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