Is CBS p.Val448Met (c.1342G>A) pathogenic?

CBS p.Val448Met (c.1342G>A) is classified Uncertain significance in CBS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-11). AlphaMissense: likely pathogenic (0.5897); Absent from gnomAD v4.1; Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is CBS p.Val448Met (c.1342G>A) in the general population?

CBS p.Val448Met (c.1342G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBS p.Val448Met (c.1342G>A)?

AlphaMissense predicts likely pathogenic (score 0.5897) — an in-silico prediction, not a clinical call.

CBS p.Val448Met

Q: What condition is associated with CBS p.Val448Met (c.1342G>A)?

CBS p.Val448Met (c.1342G>A) is associated with familial thoracic aortic aneurysm and aortic dissection, classic homocystinuria (ClinVar).

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1342G>A · rs865989946 · VCV426115

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.5897 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.5897	likely pathogenic
REVEL	0.861	moderately pathogenic-leaning
SaProt	LLR -12.55	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 4.6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 11 kb · p 6.7e-07 · regional, not allelic
Overall
CADD	29.3	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.Val448Met
Coding: c.1342G>A
MANE Select: NM_000071
dbSNP: rs865989946
Type: single nucleotide variant
Location: chr21:43058850 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 448: the cbs domain; a β-strand

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

Disease context

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: classic homocystinuria

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

CBS p.Val448fs Likely pathogenic ★ same residue
CBS p.Val448= Likely benign ★ 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-val448met (accessed [today's date]).

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