Is CTRB2 p.Ser232Pro (c.694T>C) pathogenic?

CTRB2 p.Ser232Pro (c.694T>C) is classified Uncertain significance in CTRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). AlphaMissense: likely pathogenic (0.9781); Very rare (popmax 0.00576%, nfe).

How common is CTRB2 p.Ser232Pro (c.694T>C) in the general population?

CTRB2 p.Ser232Pro (c.694T>C) is very rare (popmax 0.00576%, nfe) (gnomAD).

What do computational predictors say about CTRB2 p.Ser232Pro (c.694T>C)?

AlphaMissense predicts likely pathogenic (score 0.9781) — an in-silico prediction, not a clinical call.

CTRB2 p.Ser232Pro

c.694T>C · VCV4008108

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9781 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00576%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9781	likely pathogenic · top 5% in CTRB2
REVEL	0.967	strongly pathogenic-leaning
SaProt	LLR -15.41	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 7.9	GERP 2.3, phastCons 1
Regional constraint	o/e 1.32	unconstrained · MANE · 639 bp · p 0.0022 · regional, not allelic
Overall
CADD	24.5	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 0.00576% European (non-Finnish) · 68/1,180,004 alleles

Filtering AF 0.00462% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00422%

Overall 0.00434% 70/1,613,962 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00576%	17,353
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,078

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: CTRB2
Protein: p.Ser232Pro
Coding: c.694T>C
MANE Select: NM_001025200
Type: single nucleotide variant
Location: chr16:75204259 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI 0.36 (gnomAD)
Structure: AlphaFold pLDDT 91.79
Residue 232: a disulfide bond; the peptidase s1 domain

Full CTRB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CTRB2 p.Ala11Thr Uncertain significance ★ ⚠ same type
CTRB2 p.Ala138Thr Uncertain significance ★ ⚠ same type
CTRB2 p.Ala244Thr Uncertain significance ★ ⚠ same type
CTRB2 p.Arg131His Uncertain significance ★ ⚠ same type
CTRB2 p.Arg236Cys Uncertain significance ★ ⚠ same type
CTRB2 p.Arg236His Uncertain significance ★ ⚠ same type
CTRB2 p.Arg248Cys Uncertain significance ★ ⚠ same type
CTRB2 p.Asn167Tyr 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/ctrb2-p-ser232pro (accessed [today's date]).

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