Is CPB1 p.Arg237Cys (c.709C>T) pathogenic?

CPB1 p.Arg237Cys (c.709C>T) is classified Uncertain significance in CPB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-21). AlphaMissense: likely pathogenic (0.6848); Ultra-rare (popmax 0.0227%, afr).

How common is CPB1 p.Arg237Cys (c.709C>T) in the general population?

CPB1 p.Arg237Cys (c.709C>T) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about CPB1 p.Arg237Cys (c.709C>T)?

AlphaMissense predicts likely pathogenic (score 0.6848) — an in-silico prediction, not a clinical call.

CPB1 p.Arg237Cys

c.709C>T · rs761703950 · VCV2591470

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6848 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6848	likely pathogenic
REVEL	0.67	pathogenic-leaning
SaProt	LLR -16.67	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	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 32 kb · p 0.33 · regional, not allelic
Overall
CADD	29.0	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

Grpmax group 0.0227% African / African-American · 17/74,902 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.00521% 84/1,613,788 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,406
Middle Eastern	0.0164%	6,084
Admixed American	0.005%	19,992
European (non-Finnish)	0.005%	19,997
Remaining individualsnot grpmax-eligible	0.0048%	20,827
East Asian	0.00223%	44,894

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: CPB1
Protein: p.Arg237Cys
Coding: c.709C>T
MANE Select: NM_001871
dbSNP: rs761703950
Type: single nucleotide variant
Location: chr3:148844698 (GRCh38)
Gene constraint: LOEUF 1.167 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.71 · 2 PDB
Residue 237: the peptidase m14 domain

Full CPB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPB1 c.778+6T>C Benign ★★ same type
CPB1 p.Ile394Met Benign ★★ ⚠ same type
CPB1 p.Ala127Thr Uncertain significance ★ ⚠ same type
CPB1 p.Ala133Thr Uncertain significance ★ ⚠ same type
CPB1 p.Ala193Ser Uncertain significance ★ ⚠ same type
CPB1 p.Ala285Ser Uncertain significance ★ ⚠ same type
CPB1 p.Ala358Thr Uncertain significance ★ ⚠ same type
CPB1 p.Ala409Ser Uncertain significance ★ ⚠ same type

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/cpb1-p-arg237cys (accessed [today's date]).

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