Is CTRB1 p.Val197Met (c.589G>A) pathogenic?

CTRB1 p.Val197Met (c.589G>A) is classified Uncertain significance in CTRB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-24). AlphaMissense: likely benign (0.2144); Ultra-rare (popmax 0.0405%, afr).

How common is CTRB1 p.Val197Met (c.589G>A) in the general population?

CTRB1 p.Val197Met (c.589G>A) is ultra-rare (popmax 0.0405%, afr) (gnomAD).

What do computational predictors say about CTRB1 p.Val197Met (c.589G>A)?

AlphaMissense predicts likely benign (score 0.2144) — an in-silico prediction, not a clinical call.

CTRB1 p.Val197Met

c.589G>A · VCV3498383

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2144 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0405%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2144	likely benign
REVEL	0.433	indeterminate
SaProt	LLR -8.82	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -4
Regional constraint	o/e 0.70	unconstrained · MANE · 115 bp · p 0.029 · regional, not allelic
Overall
CADD	6.312	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 0.0405% African / African-American · 28/69,182 alleles

Filtering AF 0.0287% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0247%

Overall 0.00346% 51/1,471,950 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0405%	2,471
Remaining individualsnot grpmax-eligible	0.00879%	11,381
Finnishnot grpmax-eligible	0.00865%	11,560
South Asian	0.00123%	81,244
European (non-Finnish)	0.00111%	90,475

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.Val197Met
Coding: c.589G>A
MANE Select: NM_001906
Type: single nucleotide variant
Location: chr16:75224147 (GRCh38)
Gene constraint: LOEUF 1.902 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.90
Residue 197: 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.Val197Ala Uncertain significance ★ ⚠ same residue
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

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-val197met (accessed [today's date]).

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