Is CTRB2 p.Lys188Asn (c.564G>C) pathogenic?

CTRB2 p.Lys188Asn (c.564G>C) is classified Uncertain significance in CTRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: likely benign (0.2179); Ultra-rare (popmax 0.0722%, afr).

How common is CTRB2 p.Lys188Asn (c.564G>C) in the general population?

CTRB2 p.Lys188Asn (c.564G>C) is ultra-rare (popmax 0.0722%, afr) (gnomAD).

What do computational predictors say about CTRB2 p.Lys188Asn (c.564G>C)?

AlphaMissense predicts likely benign (score 0.2179) — an in-silico prediction, not a clinical call.

CTRB2 p.Lys188Asn

c.564G>C · VCV4235783

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2179 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0722%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2179	likely benign
REVEL	0.304	indeterminate
SaProt	LLR -9.27	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -3.1
Regional constraint	o/e 0.64	unconstrained · MANE · 100 bp · p 0.018 · regional, not allelic
Overall
CADD	14.14	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0722% African / African-American · 47/65,064 alleles

Filtering AF 0.0558% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0499%

Overall 0.0039% 53/1,359,920 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0722%	1,384
Middle Eastern	0.0246%	4,070
Remaining individualsnot grpmax-eligible	0.00558%	17,911
Admixed American	0.0043%	23,264

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.Lys188Asn
Coding: c.564G>C
MANE Select: NM_001025200
Type: single nucleotide variant
Location: chr16:75204839 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI 0.36 (gnomAD)
Structure: AlphaFold pLDDT 91.79
Residue 188: a disulfide bond; the peptidase s1 domain

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

Similar variants

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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-lys188asn (accessed [today's date]).

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