Is CBS p.Cys109Arg (c.325T>C) pathogenic?

CBS p.Cys109Arg (c.325T>C) is classified Pathogenic/Likely pathogenic in CBS (ClinVar, Multiple submitters, 13 submitters; last evaluated 2025-09-30). AlphaMissense: likely pathogenic (0.9857); Ultra-rare (popmax 0.012%, nfe); Associated with CBS-related disorder.

What condition is associated with CBS p.Cys109Arg (c.325T>C)?

CBS p.Cys109Arg (c.325T>C) is associated with CBS-related disorder, homocystinuria, classic homocystinuria (ClinVar).

How common is CBS p.Cys109Arg (c.325T>C) in the general population?

CBS p.Cys109Arg (c.325T>C) is ultra-rare (popmax 0.012%, nfe) (gnomAD).

What do computational predictors say about CBS p.Cys109Arg (c.325T>C)?

AlphaMissense predicts likely pathogenic (score 0.9857) — an in-silico prediction, not a clinical call.

CBS p.Cys109Arg

c.325T>C · rs778220779 · VCV212878

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

AlphaMissense

likely pathogenic

0.9857 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CBS-related disorder

Computational evidence

Protein change
AlphaMissense	0.9857	likely pathogenic ✓ concordant with ClinVar · top 3% in CBS
REVEL	0.979	strongly pathogenic-leaning
SaProt	LLR -12.29	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 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 5,845 bp · p 0.12 · regional, not allelic
Overall
CADD	31.0	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 0.012% European (non-Finnish) · 58/483,544 alleles

Filtering AF 0.0095% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0086%

Overall 0.00807% 60/743,160 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.012%	8,337
Remaining individualsnot grpmax-eligible	0.00589%	16,965

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.Cys109Arg
Coding: c.325T>C
MANE Select: NM_000071
dbSNP: rs778220779
Type: single nucleotide variant
Location: chr21:43066369 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 109: a β-strand; a UniProt-annotated variant site (in cbsd; loss of activity)

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

Disease context

CBS-related disorder

Also linked: homocystinuria classic homocystinuria familial thoracic aortic aneurysm and aortic dissection

Similar variants

CBS p.Cys109Tyr 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-cys109arg (accessed [today's date]).

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