Is CBS p.Gly347Ala (c.1040G>C) pathogenic?

CBS p.Gly347Ala (c.1040G>C) is classified Uncertain significance in CBS (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-02). AlphaMissense: likely pathogenic (0.8982); Absent from gnomAD v4.1; Associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED.

What condition is associated with CBS p.Gly347Ala (c.1040G>C)?

CBS p.Gly347Ala (c.1040G>C) is associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (ClinVar).

How common is CBS p.Gly347Ala (c.1040G>C) in the general population?

CBS p.Gly347Ala (c.1040G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBS p.Gly347Ala (c.1040G>C)?

AlphaMissense predicts likely pathogenic (score 0.8982) — an in-silico prediction, not a clinical call.

CBS p.Gly347Ala

c.1040G>C · rs2517413106 · VCV2164993

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8982 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Computational evidence

Protein change
AlphaMissense	0.8982	likely pathogenic
REVEL	0.962	strongly pathogenic-leaning
SaProt	LLR -13.76	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 7.4	GERP 1.1, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 11 kb · p 6.7e-07 · regional, not allelic
Overall
CADD	33.0	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.Gly347Ala
Coding: c.1040G>C
MANE Select: NM_000071
dbSNP: rs2517413106
Type: single nucleotide variant
Location: chr21:43060546 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 347: a UniProt-annotated variant site (in cbsd; protein expression is comparable to wild-type; loss of activity)

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

Similar variants

CBS p.Gly347= Likely benign ★ same residue
CBS p.Gly347Ser Pathogenic ★★ same residue
CBS p.Gly347Cys Uncertain significance ★ ⚠ same residue
CBS c.1145+1G>A Pathogenic/Likely pathogenic ★★ same condition
CBS c.1223+1G>T Pathogenic ★★ same condition
CBS c.1552+1G>A Pathogenic/Likely pathogenic ★★ same condition
CBS c.451+1G>T Likely pathogenic ★★ same condition
CBS c.531+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-gly347ala (accessed [today's date]).

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