Is CTRB2 p.Pro170Thr (c.508C>A) pathogenic?

CTRB2 p.Pro170Thr (c.508C>A) is classified Uncertain significance in CTRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-26). AlphaMissense: ambiguous (0.3935); Very rare (popmax 0.00721%, amr).

How common is CTRB2 p.Pro170Thr (c.508C>A) in the general population?

CTRB2 p.Pro170Thr (c.508C>A) is very rare (popmax 0.00721%, amr) (gnomAD).

What do computational predictors say about CTRB2 p.Pro170Thr (c.508C>A)?

AlphaMissense predicts ambiguous (score 0.3935) — an in-silico prediction, not a clinical call.

CTRB2 p.Pro170Thr

c.508C>A · VCV3498388

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3935 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00721%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3935	ambiguous
REVEL	0.723	pathogenic-leaning
SaProt	LLR -7.89	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.3	GERP -1.5, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 100 bp · p 0.018 · regional, not allelic
Overall
CADD	20.8	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 0.00721% Admixed American · 3/41,622 alleles

Filtering AF 0.00191% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00103%

Overall 0.00128% 14/1,096,818 alleles · very rare exomes 14/985,140 · genomes 0/111,678 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00721%	13,874
Remaining individualsnot grpmax-eligible	0.00221%	45,164
European (non-Finnish)	0.00129%	77,584

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.Pro170Thr
Coding: c.508C>A
MANE Select: NM_001025200
Type: single nucleotide variant
Location: chr16:75204895 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI 0.36 (gnomAD)
Structure: AlphaFold pLDDT 91.79
Residue 170: 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-pro170thr (accessed [today's date]).

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