Is CBS p.Arg132Cys (c.394C>T) pathogenic?

CBS p.Arg132Cys (c.394C>T) is classified Conflicting classifications of pathogenicity in CBS (ClinVar, Conflicting submitters, 17 submitters; last evaluated 2025-09-11). AlphaMissense: likely benign (0.1189); Ultra-rare (popmax 0.0818%, nfe); Associated with classic homocystinuria.

What condition is associated with CBS p.Arg132Cys (c.394C>T)?

CBS p.Arg132Cys (c.394C>T) is associated with classic homocystinuria, intellectual disability, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is CBS p.Arg132Cys (c.394C>T) in the general population?

CBS p.Arg132Cys (c.394C>T) is ultra-rare (popmax 0.0818%, nfe) (gnomAD).

What do computational predictors say about CBS p.Arg132Cys (c.394C>T)?

AlphaMissense predicts likely benign (score 0.1189) — an in-silico prediction, not a clinical call.

CBS p.Arg132Cys

Q: How is Homocystinuria due to cystathionine beta-synthase deficiency inherited?

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

c.394C>T · rs140002610 · VCV212843

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 17 submitters

AlphaMissense

likely benign

0.1189 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0818%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

classic homocystinuria

Computational evidence

Protein change
AlphaMissense	0.1189	likely benign
REVEL	0.746	pathogenic-leaning
SaProt	LLR -11.87	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
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	23.1	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 0.0818% European (non-Finnish) · 595/727,750 alleles

Filtering AF 0.0762% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0742%

Overall 0.0611% 638/1,044,308 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0818%	1,223
East Asian	0.0498%	2,007
Remaining individualsnot grpmax-eligible	0.0206%	4,862
African / African-American	0.0187%	5,333
Finnishnot grpmax-eligible	0.0113%	8,833
Admixed American	0.00189%	52,862
South Asian	0.00135%	74,132

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.Arg132Cys
Coding: c.394C>T
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

classic homocystinuria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual disability familial thoracic aortic aneurysm and aortic dissection

For Homocystinuria due to cystathionine beta-synthase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

CBS p.Arg132His Uncertain significance ★★ ⚠ same residue
CBS p.Arg132Ser Uncertain significance ★★ ⚠ same residue
CBS p.Arg132= 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

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-arg132cys (accessed [today's date]).

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