Is CBS p.Arg336His (c.1007G>A) pathogenic?

CBS p.Arg336His (c.1007G>A) is classified Pathogenic/Likely pathogenic in CBS (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-22). AlphaMissense: ambiguous (0.4079); Ultra-rare (popmax 0.0505%); Associated with homocystinuria.

What condition is associated with CBS p.Arg336His (c.1007G>A)?

CBS p.Arg336His (c.1007G>A) is associated with homocystinuria, classic homocystinuria (ClinVar).

How common is CBS p.Arg336His (c.1007G>A) in the general population?

CBS p.Arg336His (c.1007G>A) is ultra-rare (popmax 0.0505%) (gnomAD).

What do computational predictors say about CBS p.Arg336His (c.1007G>A)?

AlphaMissense predicts ambiguous (score 0.4079) — an in-silico prediction, not a clinical call.

CBS p.Arg336His

c.1007G>A · rs760417941 · VCV371147

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.4079 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0505%)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

homocystinuria

Computational evidence

Protein change
AlphaMissense	0.4079	ambiguous
REVEL	0.953	strongly pathogenic-leaning
SaProt	LLR -12.16	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 3.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 11 kb · p 6.7e-07 · regional, not allelic
Overall
CADD	26.0	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 0.0505%

Overall 0.0505% 1/1,980 alleles · ultra-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.Arg336His
Coding: c.1007G>A
MANE Select: NM_000071
dbSNP: rs760417941
Type: single nucleotide variant
Location: chr21:43062343 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 336: an α-helix; a UniProt-annotated variant site (in cbsd; protein expression is comparable to wild-type; loss of activity; absent capacity to form multimeric quaternary structure); a UniProt-annotated variant site (in cbsd; mild form; no effect on expression; exhibits an activity lower than 4% of the wild-type enzyme; altered stimulation by adomet; absent capacity to form multimeric quaternary structure)

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

Disease context

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

Also linked: classic homocystinuria

Similar variants

CBS p.Arg336Pro Pathogenic/Likely pathogenic ★★ same residue
CBS p.Arg336_Met337insTer Likely pathogenic same residue
CBS p.Arg336Ser Likely pathogenic ★ same residue
CBS p.Arg336Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CBS p.Arg336= 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

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-arg336his (accessed [today's date]).

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