Is CTRB1 p.Arg131Cys (c.391C>T) pathogenic?

CTRB1 p.Arg131Cys (c.391C>T) is classified Uncertain significance in CTRB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-25). AlphaMissense: likely benign (0.2377); Very rare (popmax 0.00929%, nfe).

How common is CTRB1 p.Arg131Cys (c.391C>T) in the general population?

CTRB1 p.Arg131Cys (c.391C>T) is very rare (popmax 0.00929%, nfe) (gnomAD).

What do computational predictors say about CTRB1 p.Arg131Cys (c.391C>T)?

AlphaMissense predicts likely benign (score 0.2377) — an in-silico prediction, not a clinical call.

CTRB1 p.Arg131Cys

c.391C>T · VCV4008097

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2377 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00929%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2377	likely benign
REVEL	0.378	indeterminate
SaProt	LLR -10.79	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.2	GERP -4.4
Regional constraint	o/e 0.13	constrained · MANE · 1,089 bp · p 5.9e-17 · regional, not allelic
Overall
CADD	14.88	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 0.00929% European (non-Finnish) · 40/430,766 alleles

Filtering AF 0.00699% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00616%

Overall 0.00681% 47/690,384 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00929%	10,769
East Asian	0.00893%	11,193
Remaining individualsnot grpmax-eligible	0.00627%	15,958
Admixed American	0.00361%	27,682
South Asian	0.00176%	56,846

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: CTRB1
Protein: p.Arg131Cys
Coding: c.391C>T
MANE Select: NM_001906
Type: single nucleotide variant
Location: chr16:75223523 (GRCh38)
Gene constraint: LOEUF 1.902 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.90
Residue 131: a disulfide bond; the peptidase s1 domain

Full CTRB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CTRB1 p.Arg131His Uncertain significance ★ ⚠ same residue
CTRB1 p.Ala104Asp Uncertain significance ★ ⚠ same type
CTRB1 p.Ala138Thr Uncertain significance ★ ⚠ same type
CTRB1 p.Ala144Thr Uncertain significance ★ ⚠ same type
CTRB1 p.Ala150Ser Uncertain significance ★ ⚠ same type
CTRB1 p.Ala177Val Uncertain significance ★ ⚠ same type
CTRB1 p.Ala261Val Uncertain significance ★ ⚠ same type
CTRB1 p.Ala40Thr 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/ctrb1-p-arg131cys (accessed [today's date]).

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