Is CBS p.Arg125Trp (c.373C>T) pathogenic?

CBS p.Arg125Trp (c.373C>T) is classified Pathogenic/Likely pathogenic in CBS (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-06-23). AlphaMissense: likely benign (0.2966); Very rare (popmax 0.00197%, amr); Associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED.

What condition is associated with CBS p.Arg125Trp (c.373C>T)?

CBS p.Arg125Trp (c.373C>T) is associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED, homocystinuria, classic homocystinuria (ClinVar).

How common is CBS p.Arg125Trp (c.373C>T) in the general population?

CBS p.Arg125Trp (c.373C>T) is very rare (popmax 0.00197%, amr) (gnomAD).

What do computational predictors say about CBS p.Arg125Trp (c.373C>T)?

AlphaMissense predicts likely benign (score 0.2966) — an in-silico prediction, not a clinical call.

CBS p.Arg125Trp

c.373C>T · rs886057100 · VCV340089

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.2966 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00197%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Computational evidence

Protein change
AlphaMissense	0.2966	likely benign ⚠ discordant with ClinVar
REVEL	0.937	strongly pathogenic-leaning
SaProt	LLR -12.62	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.26, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 46 bp · p 4.9e-05 · regional, not allelic
Overall
CADD	25.9	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 0.00197% Admixed American · 1/50,714 alleles

Overall 0.000121% 1/829,620 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.Arg125Trp
Coding: c.373C>T
MANE Select: NM_000071
dbSNP: rs886057100
Type: single nucleotide variant
Location: chr21:43066321 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 125: an α-helix; a UniProt-annotated variant site (in cbsd); a UniProt-annotated variant site (in cbsd; severe form; when linked with d-131 moderate form; loss of cystathionine beta-synthase activity; decreased homotetramer formation); a UniProt-annotated variant site (in cbsd; exhibits an activity lower than 4% of the wild-type enzyme; absent capacity to form multimeric quaternary structure)

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

Disease context

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: homocystinuria classic homocystinuria

Similar variants

CBS p.Arg125Gln Pathogenic ★★ ⚠ same residue
CBS p.Arg125Pro 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-arg125trp (accessed [today's date]).

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