Is CTRB2 p.Gly43Ser (c.127G>A) pathogenic?

CTRB2 p.Gly43Ser (c.127G>A) is classified Uncertain significance in CTRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-14). AlphaMissense: likely benign (0.2896); Ultra-rare (popmax 0.0235%, afr).

How common is CTRB2 p.Gly43Ser (c.127G>A) in the general population?

CTRB2 p.Gly43Ser (c.127G>A) is ultra-rare (popmax 0.0235%, afr) (gnomAD).

What do computational predictors say about CTRB2 p.Gly43Ser (c.127G>A)?

AlphaMissense predicts likely benign (score 0.2896) — an in-silico prediction, not a clinical call.

CTRB2 p.Gly43Ser

c.127G>A · rs755863314 · VCV2394637

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2896 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0235%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2896	likely benign
REVEL	0.726	pathogenic-leaning
SaProt	LLR -12.38	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 0.98, phastCons 0.72
Regional constraint	o/e 0.79	unconstrained · MANE · 1,158 bp · p 0.067 · regional, not allelic
Overall
CADD	18.41	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 0.0235% African / African-American · 17/72,478 alleles

Filtering AF 0.0149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0122%

Overall 0.00423% 65/1,535,938 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0235%	4,263
Remaining individualsnot grpmax-eligible	0.0101%	9,878
European (non-Finnish)	0.00369%	27,066

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.Gly43Ser
Coding: c.127G>A
MANE Select: NM_001025200
dbSNP: rs755863314
Type: single nucleotide variant
Location: chr16:75206119 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI 0.36 (gnomAD)
Structure: AlphaFold pLDDT 91.79
Residue 43: the peptidase s1 domain; a disulfide bond

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

Similar variants

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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
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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-gly43ser (accessed [today's date]).

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