Is CTRB2 p.Gly56Ser (c.166G>A) pathogenic?

CTRB2 p.Gly56Ser (c.166G>A) is classified Uncertain significance in CTRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-25). AlphaMissense: likely benign (0.2748); Very rare (popmax 0.00541%, afr).

How common is CTRB2 p.Gly56Ser (c.166G>A) in the general population?

CTRB2 p.Gly56Ser (c.166G>A) is very rare (popmax 0.00541%, afr) (gnomAD).

What do computational predictors say about CTRB2 p.Gly56Ser (c.166G>A)?

AlphaMissense predicts likely benign (score 0.2748) — an in-silico prediction, not a clinical call.

CTRB2 p.Gly56Ser

c.166G>A · VCV4235788

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2748 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00541%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2748	likely benign
REVEL	0.691	pathogenic-leaning
SaProt	LLR -8.51	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP 1, phastCons 0.44
Regional constraint	o/e 0.79	unconstrained · MANE · 1,158 bp · p 0.067 · regional, not allelic
Overall
CADD	25.9	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 0.00541% African / African-American · 3/55,424 alleles

Filtering AF 0.00144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000698%

Overall 0.00135% 13/962,214 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0067%	14,929
African / African-Americangrpmax	0.00541%	18,475
South Asian	0.00341%	29,305
East Asian	0.00266%	37,588
European (non-Finnish)	0.000602%	166,125

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Gly56Ser
Coding: c.166G>A
MANE Select: NM_001025200
Type: single nucleotide variant
Location: chr16:75205983 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI 0.36 (gnomAD)
Structure: AlphaFold pLDDT 91.79
Residue 56: the peptidase s1 domain; a disulfide bond

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-gly56ser (accessed [today's date]).

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