Is CBS p.Pro312His (c.935C>A) pathogenic?

CBS p.Pro312His (c.935C>A) is classified Conflicting classifications of pathogenicity in CBS (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-03-10). AlphaMissense: likely pathogenic (0.9806); Absent from gnomAD v4.1; Associated with inborn errors of metabolism.

What condition is associated with CBS p.Pro312His (c.935C>A)?

CBS p.Pro312His (c.935C>A) is associated with inborn errors of metabolism, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is CBS p.Pro312His (c.935C>A) in the general population?

CBS p.Pro312His (c.935C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CBS p.Pro312His (c.935C>A)?

AlphaMissense predicts likely pathogenic (score 0.9806) — an in-silico prediction, not a clinical call.

CBS p.Pro312His

c.935C>A · rs761787042 · VCV2447115

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9806 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inborn errors of metabolism

Computational evidence

Protein change
AlphaMissense	0.9806	likely pathogenic · top 4% in CBS
REVEL	0.905	moderately pathogenic-leaning
SaProt	LLR -15.72	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 8.3	GERP 1.1, phastCons 1
Regional constraint	o/e 0.00	constrained · MANE · 11 kb · p 6.7e-07 · regional, not allelic
Overall
CADD	32.0	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

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.Pro312His
Coding: c.935C>A
MANE Select: NM_000071
dbSNP: rs761787042
Type: single nucleotide variant
Location: chr21:43062972 (GRCh38)
Structure: AlphaFold pLDDT 90.15 · 28 PDB

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

Disease context

inborn errors of metabolism — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial thoracic aortic aneurysm and aortic dissection

Similar variants

CBS p.Pro312= Likely benign ★ same residue
CBS c.1224-2A>C Pathogenic ★★ same condition
CBS c.954+1G>A Pathogenic/Likely pathogenic ★★ same condition
CBS p.Ala114Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
CBS p.Ala288Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
CBS p.Ala331Glu Pathogenic/Likely pathogenic ★★ same condition
CBS p.Arg121His Pathogenic/Likely pathogenic ★★ same condition
CBS p.Arg125Gln 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-pro312his (accessed [today's date]).

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