Is CBS p.Arg121His (c.362G>A) pathogenic?

CBS p.Arg121His (c.362G>A) is classified Pathogenic/Likely pathogenic in CBS (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-02-05). AlphaMissense: likely pathogenic (0.7955); Very rare (popmax 0.00392%, afr); Associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED.

What condition is associated with CBS p.Arg121His (c.362G>A)?

CBS p.Arg121His (c.362G>A) is associated with HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED, homocystinuria, classic homocystinuria (ClinVar).

How common is CBS p.Arg121His (c.362G>A) in the general population?

CBS p.Arg121His (c.362G>A) is very rare (popmax 0.00392%, afr) (gnomAD).

What do computational predictors say about CBS p.Arg121His (c.362G>A)?

AlphaMissense predicts likely pathogenic (score 0.7955) — an in-silico prediction, not a clinical call.

CBS p.Arg121His

c.362G>A · rs770095972 · VCV188948

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.7955 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00392%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Computational evidence

Protein change
AlphaMissense	0.7955	likely pathogenic ✓ concordant with ClinVar
REVEL	0.964	strongly pathogenic-leaning
SaProt	LLR -14.27	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 5.7	GERP 1.3, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 46 bp · p 4.9e-05 · regional, not allelic
Overall
CADD	33.0	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 0.00392% African / African-American · 1/25,498 alleles

Filtering AF 0.000138% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.8e-05%

Overall 0.000885% 7/791,080 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00392%	25,498
Remaining individualsnot grpmax-eligible	0.00263%	37,980
Finnishnot grpmax-eligible	0.0025%	39,932
Admixed American	0.00204%	49,100
European (non-Finnish)	0.000519%	192,853

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.Arg121His
Coding: c.362G>A
MANE Select: NM_000071
dbSNP: rs770095972
Type: single nucleotide variant
Location: chr21:43066332 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB
Residue 121: an α-helix; a UniProt-annotated variant site (in cbsd); a UniProt-annotated variant site (in cbsd; mild form)

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

Also linked: homocystinuria classic homocystinuria familial thoracic aortic aneurysm and aortic dissection

Similar variants

CBS p.Arg121Cys Pathogenic/Likely pathogenic ★★ same residue
CBS p.Arg121Gly Pathogenic/Likely pathogenic ★★ same residue
CBS p.Arg121Leu Pathogenic/Likely pathogenic ★★ 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-arg121his (accessed [today's date]).

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