Is CTRB2 p.Val206Ile (c.616G>A) pathogenic?

CTRB2 p.Val206Ile (c.616G>A) is classified Uncertain significance in CTRB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-17). AlphaMissense: likely benign (0.0854); Rare (popmax 0.889%, mid).

How common is CTRB2 p.Val206Ile (c.616G>A) in the general population?

CTRB2 p.Val206Ile (c.616G>A) is rare (popmax 0.889%, mid) (gnomAD).

What do computational predictors say about CTRB2 p.Val206Ile (c.616G>A)?

AlphaMissense predicts likely benign (score 0.0854) — an in-silico prediction, not a clinical call.

CTRB2 p.Val206Ile

c.616G>A · VCV3837273

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0854 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.889%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0854	likely benign
REVEL	0.289	benign-leaning
SaProt	LLR -7.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP 0.87
Regional constraint	o/e 1.32	unconstrained · MANE · 639 bp · p 0.0022 · regional, not allelic
Overall
CADD	17.13	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.889% Middle Eastern · 36/4,050 alleles

Filtering AF 0.66% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.581%

Overall 0.0618% 876/1,418,540 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.889%	112
Ashkenazi Jewishnot grpmax-eligible	0.394%	254
Remaining individualsnot grpmax-eligible	0.126%	794
South Asian	0.12%	836
Admixed American	0.0956%	1,046
European (non-Finnish)	0.0486%	2,056
African / African-American	0.042%	2,382
Finnishnot grpmax-eligible	0.00185%	54,154

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.Val206Ile
Coding: c.616G>A
MANE Select: NM_001025200
Type: single nucleotide variant
Location: chr16:75204787 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI 0.36 (gnomAD)
Structure: AlphaFold pLDDT 91.79
Residue 206: a disulfide bond; 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-val206ile (accessed [today's date]).

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