Is CTRB2 p.Ile230Thr (c.689T>C) pathogenic?

CTRB2 p.Ile230Thr (c.689T>C) is classified Uncertain significance in CTRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-18). AlphaMissense: likely pathogenic (0.7367); Ultra-rare (popmax 0.016%, afr).

How common is CTRB2 p.Ile230Thr (c.689T>C) in the general population?

CTRB2 p.Ile230Thr (c.689T>C) is ultra-rare (popmax 0.016%, afr) (gnomAD).

What do computational predictors say about CTRB2 p.Ile230Thr (c.689T>C)?

AlphaMissense predicts likely pathogenic (score 0.7367) — an in-silico prediction, not a clinical call.

CTRB2 p.Ile230Thr

c.689T>C · rs150266828 · VCV3078731

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7367 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7367	likely pathogenic
REVEL	0.947	strongly pathogenic-leaning
SaProt	LLR -8.37	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 2.3, phastCons 1
Regional constraint	o/e 1.32	unconstrained · MANE · 639 bp · p 0.0022 · regional, not allelic
Overall
CADD	23.1	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 0.016% African / African-American · 12/74,976 alleles

Filtering AF 0.00921% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00721%

Overall 0.00211% 34/1,613,974 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,248
Admixed American	0.0117%	8,572
Remaining individualsnot grpmax-eligible	0.008%	12,500
South Asian	0.00439%	22,769
European (non-Finnish)	0.000508%	196,661

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.Ile230Thr
Coding: c.689T>C
MANE Select: NM_001025200
dbSNP: rs150266828
Type: single nucleotide variant
Location: chr16:75204264 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI 0.36 (gnomAD)
Structure: AlphaFold pLDDT 91.79
Residue 230: 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-ile230thr (accessed [today's date]).

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