Is CBS p.Gly85Arg (c.253G>A) pathogenic?

CBS p.Gly85Arg (c.253G>A) is classified Pathogenic in CBS (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.7481); Very rare (popmax 0.00217%, sas); Associated with classic homocystinuria.

What condition is associated with CBS p.Gly85Arg (c.253G>A)?

CBS p.Gly85Arg (c.253G>A) is associated with classic homocystinuria (ClinVar).

How common is CBS p.Gly85Arg (c.253G>A) in the general population?

CBS p.Gly85Arg (c.253G>A) is very rare (popmax 0.00217%, sas) (gnomAD).

What do computational predictors say about CBS p.Gly85Arg (c.253G>A)?

AlphaMissense predicts likely pathogenic (score 0.7481) — an in-silico prediction, not a clinical call.

CBS p.Gly85Arg

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.253G>A · rs863223435 · VCV212874

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.7481 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00217%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

classic homocystinuria

Computational evidence

Protein change
AlphaMissense	0.7481	likely pathogenic ✓ concordant with ClinVar
REVEL	0.94	strongly pathogenic-leaning
SaProt	LLR -13.80	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 5.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 5,845 bp · p 0.12 · regional, not allelic
Overall
CADD	29.1	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 0.00217% South Asian · 1/46,164 alleles

Overall 0.000542% 2/368,804 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00217%	46,164
European (non-Finnish)	0.000439%	227,652

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.Gly85Arg
Coding: c.253G>A
MANE Select: NM_000071
dbSNP: rs863223435
Type: single nucleotide variant
Location: chr21:43068572 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 85: a β-strand; a UniProt-annotated variant site (in cbsd; loss of cystathionine beta-synthase activity)

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 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
CBS c.209+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-gly85arg (accessed [today's date]).

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