Is CBS p.Gly151Arg (c.451G>A) pathogenic?

CBS p.Gly151Arg (c.451G>A) is classified Pathogenic in CBS (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-25). AlphaMissense: likely pathogenic (0.9922); Very rare (popmax 0.00496%, afr); Associated with classic homocystinuria.

What condition is associated with CBS p.Gly151Arg (c.451G>A)?

CBS p.Gly151Arg (c.451G>A) is associated with classic homocystinuria, homocystinuria, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is CBS p.Gly151Arg (c.451G>A) in the general population?

CBS p.Gly151Arg (c.451G>A) is very rare (popmax 0.00496%, afr) (gnomAD).

What do computational predictors say about CBS p.Gly151Arg (c.451G>A)?

AlphaMissense predicts likely pathogenic (score 0.9922) — an in-silico prediction, not a clinical call.

CBS p.Gly151Arg

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.451G>A · rs373782713 · VCV863694

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9922 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00496%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

classic homocystinuria

Computational evidence

Protein change
AlphaMissense	0.9922	likely pathogenic ✓ concordant with ClinVar · top 1% in CBS
REVEL	0.975	strongly pathogenic-leaning
SaProt	LLR -17.45	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 1.3, phastCons 1
Regional constraint	o/e 0.24	constrained · MANE · 1,046 bp · p 7.5e-10 · regional, not allelic
Overall
CADD	34.0	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 0.00496% African / African-American · 2/40,356 alleles

Filtering AF 0.00104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000849%

Overall 0.00178% 24/1,349,764 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00496%	20,178
East Asian	0.00457%	21,864
Remaining individualsnot grpmax-eligible	0.00376%	26,615
Admixed American	0.00181%	55,364
European (non-Finnish)	0.00171%	58,636

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.Gly151Arg
Coding: c.451G>A
MANE Select: NM_000071
dbSNP: rs373782713
Type: single nucleotide variant
Location: chr21:43066243 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 151: an α-helix; a UniProt-annotated variant site (in cbsd)

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: homocystinuria 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.Gly151Trp Uncertain significance ★ ⚠ same residue
CBS p.Gly151Val Uncertain significance ★ ⚠ 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

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-gly151arg (accessed [today's date]).

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