Is CTRB1 p.Gly215Ser (c.643G>A) pathogenic?

CTRB1 p.Gly215Ser (c.643G>A) is classified Uncertain significance in CTRB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: ambiguous (0.5095); Ultra-rare (popmax 0.0191%, nfe).

How common is CTRB1 p.Gly215Ser (c.643G>A) in the general population?

CTRB1 p.Gly215Ser (c.643G>A) is ultra-rare (popmax 0.0191%, nfe) (gnomAD).

What do computational predictors say about CTRB1 p.Gly215Ser (c.643G>A)?

AlphaMissense predicts ambiguous (score 0.5095) — an in-silico prediction, not a clinical call.

CTRB1 p.Gly215Ser

c.643G>A · rs375112297 · VCV2364797

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5095 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0191%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5095	ambiguous
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -10.81	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.77, phastCons 1
Regional constraint	o/e 1.41	unconstrained · MANE · 688 bp · p 0.00038 · regional, not allelic
Overall
CADD	25.2	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 0.0191% European (non-Finnish) · 225/1,178,624 alleles

Filtering AF 0.017% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0162%

Overall 0.0156% 251/1,610,128 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0191%	5,238
Admixed American	0.0169%	5,900
Remaining individualsnot grpmax-eligible	0.0112%	8,902
African / African-American	0.00668%	14,964
South Asian	0.00441%	22,686

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: CTRB1
Protein: p.Gly215Ser
Coding: c.643G>A
MANE Select: NM_001906
dbSNP: rs375112297
Type: single nucleotide variant
Location: chr16:75224717 (GRCh38)
Gene constraint: LOEUF 1.902 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.90
Residue 215: a disulfide bond; the peptidase s1 domain

Full CTRB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CTRB1 p.Ala104Asp Uncertain significance ★ ⚠ same type
CTRB1 p.Ala138Thr Uncertain significance ★ ⚠ same type
CTRB1 p.Ala144Thr Uncertain significance ★ ⚠ same type
CTRB1 p.Ala150Ser Uncertain significance ★ ⚠ same type
CTRB1 p.Ala177Val Uncertain significance ★ ⚠ same type
CTRB1 p.Ala261Val Uncertain significance ★ ⚠ same type
CTRB1 p.Ala40Thr Uncertain significance ★ ⚠ same type
CTRB1 p.Arg131Cys 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/ctrb1-p-gly215ser (accessed [today's date]).

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