Is CTRB2 p.Val139Met (c.415G>A) pathogenic?

CTRB2 p.Val139Met (c.415G>A) is classified Uncertain significance in CTRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-09). AlphaMissense: likely pathogenic (0.7148); Ultra-rare (popmax 0.0917%, eas).

How common is CTRB2 p.Val139Met (c.415G>A) in the general population?

CTRB2 p.Val139Met (c.415G>A) is ultra-rare (popmax 0.0917%, eas) (gnomAD).

What do computational predictors say about CTRB2 p.Val139Met (c.415G>A)?

AlphaMissense predicts likely pathogenic (score 0.7148) — an in-silico prediction, not a clinical call.

CTRB2 p.Val139Met

c.415G>A · VCV4008102

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7148 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0917%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7148	likely pathogenic
REVEL	0.778	moderately pathogenic-leaning
SaProt	LLR -14.04	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.35	GERP 1, phastCons 0.019
Regional constraint	o/e 0.09	constrained · MANE · 1,077 bp · p 4.7e-13 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0917% East Asian · 25/27,264 alleles

Filtering AF 0.0637% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0544%

Overall 0.00964% 41/425,184 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0917%	1,091
South Asian	0.0356%	2,808
Admixed American	0.00441%	22,690

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.Val139Met
Coding: c.415G>A
MANE Select: NM_001025200
Type: single nucleotide variant
Location: chr16:75205414 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI 0.36 (gnomAD)
Structure: AlphaFold pLDDT 91.79
Residue 139: 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-val139met (accessed [today's date]).

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