Is CBS p.Val118Met (c.352G>A) pathogenic?

CBS p.Val118Met (c.352G>A) is classified Uncertain significance in CBS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-09). AlphaMissense: ambiguous (0.3461); Very rare (popmax 0.00146%, sas); Associated with classic homocystinuria.

What condition is associated with CBS p.Val118Met (c.352G>A)?

CBS p.Val118Met (c.352G>A) is associated with classic homocystinuria (ClinVar).

How common is CBS p.Val118Met (c.352G>A) in the general population?

CBS p.Val118Met (c.352G>A) is very rare (popmax 0.00146%, sas) (gnomAD).

What do computational predictors say about CBS p.Val118Met (c.352G>A)?

AlphaMissense predicts ambiguous (score 0.3461) — an in-silico prediction, not a clinical call.

CBS p.Val118Met

Q: How is Homocystinuria due to cystathionine beta-synthase deficiency inherited?

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

c.352G>A · rs763385546 · VCV340090

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3461 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00146%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

classic homocystinuria

Computational evidence

Protein change
AlphaMissense	0.3461	ambiguous
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -13.01	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.3, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 46 bp · p 4.9e-05 · regional, not allelic
Overall
CADD	29.2	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 0.00146% South Asian · 1/68,654 alleles

Filtering AF 0.000143% ClinGen BA1/BS1 input FAF95, joint · FAF99 4e-05%

Overall 0.000518% 4/772,506 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00146%	68,654
European (non-Finnish)	0.000536%	186,431

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.Val118Met
Coding: c.352G>A
MANE Select: NM_000071
dbSNP: rs763385546
Type: single nucleotide variant
Location: chr21:43066342 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB

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

Disease context

classic homocystinuria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Homocystinuria due to cystathionine beta-synthase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

CBS p.Val118fs Likely pathogenic ★ same residue
CBS p.Val118Leu Uncertain significance ★ ⚠ same residue
CBS p.Val118= 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

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-val118met (accessed [today's date]).

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