Is CBS p.Arg125Pro (c.374G>C) pathogenic?

CBS p.Arg125Pro (c.374G>C) is classified Uncertain significance in CBS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-05). AlphaMissense: likely pathogenic (0.9726); Absent from gnomAD v4.1.

How common is CBS p.Arg125Pro (c.374G>C) in the general population?

CBS p.Arg125Pro (c.374G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBS p.Arg125Pro (c.374G>C)?

AlphaMissense predicts likely pathogenic (score 0.9726) — an in-silico prediction, not a clinical call.

CBS p.Arg125Pro

c.374G>C · rs781444670 · VCV3251498

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9726 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9726	likely pathogenic · top 6% in CBS
REVEL	0.955	strongly pathogenic-leaning
SaProt	LLR -14.26	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 4.7	GERP 1.3, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 46 bp · p 4.9e-05 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CBS
Protein: p.Arg125Pro
Coding: c.374G>C
MANE Select: NM_000071
dbSNP: rs781444670
Type: single nucleotide variant
Location: chr21:43066320 (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

Similar variants

CBS p.Arg125Gln Pathogenic ★★ ⚠ same residue
CBS p.Arg125Trp Pathogenic/Likely pathogenic ★★ ⚠ same residue
CBS c.1145+1G>A Pathogenic/Likely pathogenic ★★ same type
CBS c.1223+1G>T Pathogenic ★★ same type
CBS c.1224-2A>C Pathogenic ★★ same type
CBS c.1358+1G>A Pathogenic ★★ same type
CBS c.1359-1G>C Pathogenic/Likely pathogenic ★★ same type
CBS c.1468-1G>A Likely pathogenic ★★ same type

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-arg125pro (accessed [today's date]).

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