Is CBS p.Arg266Gly (c.796A>G) pathogenic?

CBS p.Arg266Gly (c.796A>G) is classified Likely pathogenic in CBS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-18). AlphaMissense: likely pathogenic (0.8209); Very rare (popmax 0.00443%, eas); Associated with classic homocystinuria.

What condition is associated with CBS p.Arg266Gly (c.796A>G)?

CBS p.Arg266Gly (c.796A>G) is associated with classic homocystinuria (ClinVar).

How common is CBS p.Arg266Gly (c.796A>G) in the general population?

CBS p.Arg266Gly (c.796A>G) is very rare (popmax 0.00443%, eas) (gnomAD).

What do computational predictors say about CBS p.Arg266Gly (c.796A>G)?

AlphaMissense predicts likely pathogenic (score 0.8209) — an in-silico prediction, not a clinical call.

CBS p.Arg266Gly

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.796A>G · rs2517436554 · VCV2680419

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8209 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00443%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

classic homocystinuria

Computational evidence

Protein change
AlphaMissense	0.8209	likely pathogenic ✓ concordant with ClinVar
REVEL	0.942	strongly pathogenic-leaning
SaProt	LLR -12.55	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 1.3	GERP -1.2, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 11 kb · p 6.7e-07 · regional, not allelic
Overall
CADD	24.8	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 0.00443% East Asian · 1/22,570 alleles

Overall 0.000486% 1/205,788 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.Arg266Gly
Coding: c.796A>G
MANE Select: NM_000071
dbSNP: rs2517436554
Type: single nucleotide variant
Location: chr21:43063932 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 266: an α-helix; a UniProt-annotated variant site (in cbsd); a UniProt-annotated variant site (in cbsd; mild form; decreased cystathionine beta-synthase activity; decreased homotetramer formation; no effect on heme-binding; decreased stability)

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

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.Arg266Lys Pathogenic/Likely pathogenic ★★ ⚠ 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-arg266gly (accessed [today's date]).

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