Is CBS p.Arg121Cys (c.361C>T) pathogenic?

CBS p.Arg121Cys (c.361C>T) is classified Pathogenic/Likely pathogenic in CBS (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-20). AlphaMissense: likely pathogenic (0.7974); Very rare (popmax 0.00482%, nfe); Associated with CBS-related disorder.

What condition is associated with CBS p.Arg121Cys (c.361C>T)?

CBS p.Arg121Cys (c.361C>T) is associated with CBS-related disorder, homocystinuria, classic homocystinuria (ClinVar).

How common is CBS p.Arg121Cys (c.361C>T) in the general population?

CBS p.Arg121Cys (c.361C>T) is very rare (popmax 0.00482%, nfe) (gnomAD).

What do computational predictors say about CBS p.Arg121Cys (c.361C>T)?

AlphaMissense predicts likely pathogenic (score 0.7974) — an in-silico prediction, not a clinical call.

CBS p.Arg121Cys

c.361C>T · rs775992753 · VCV212842

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.7974 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00482%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CBS-related disorder

Computational evidence

Protein change
AlphaMissense	0.7974	likely pathogenic ✓ concordant with ClinVar
REVEL	0.938	strongly pathogenic-leaning
SaProt	LLR -16.71	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 9.5	GERP 0.25, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 46 bp · p 4.9e-05 · regional, not allelic
Overall
CADD	33.0	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 0.00482% European (non-Finnish) · 28/581,320 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00287%

Overall 0.00352% 28/794,602 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.Arg121Cys
Coding: c.361C>T
MANE Select: NM_000071
dbSNP: rs775992753
Type: single nucleotide variant
Location: chr21:43066333 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 121: an α-helix; a UniProt-annotated variant site (in cbsd); a UniProt-annotated variant site (in cbsd; mild form)

Full CBS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CBS-related disorder

Also linked: homocystinuria classic homocystinuria

Similar variants

CBS p.Arg121His Pathogenic/Likely pathogenic ★★ same residue
CBS p.Arg121Leu Pathogenic/Likely pathogenic ★★ same residue
CBS p.Arg121Gly 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

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-arg121cys (accessed [today's date]).

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