Is CTRB1 p.Val197Ala (c.590T>C) pathogenic?

CTRB1 p.Val197Ala (c.590T>C) is classified Uncertain significance in CTRB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-05). AlphaMissense: likely benign (0.1253); Very rare (popmax 0.00434%, afr).

How common is CTRB1 p.Val197Ala (c.590T>C) in the general population?

CTRB1 p.Val197Ala (c.590T>C) is very rare (popmax 0.00434%, afr) (gnomAD).

What do computational predictors say about CTRB1 p.Val197Ala (c.590T>C)?

AlphaMissense predicts likely benign (score 0.1253) — an in-silico prediction, not a clinical call.

CTRB1 p.Val197Ala

c.590T>C · rs1941683318 · VCV2255237

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1253 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00434%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1253	likely benign
REVEL	0.152	moderately benign-leaning
SaProt	LLR -6.69	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 -10	GERP -4
Regional constraint	o/e 0.70	unconstrained · MANE · 115 bp · p 0.029 · regional, not allelic
Overall
CADD	1.782	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 0.00434% African / African-American · 3/69,142 alleles

Filtering AF 0.00115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000619%

Overall 0.000204% 3/1,473,984 alleles · very rare exomes 2/1,328,664 · genomes 1/145,320 · joint denominator

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.Val197Ala
Coding: c.590T>C
MANE Select: NM_001906
dbSNP: rs1941683318
Type: single nucleotide variant
Location: chr16:75224148 (GRCh38)
Gene constraint: LOEUF 1.902 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.90
Residue 197: the peptidase s1 domain

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

Similar variants

CTRB1 p.Val197Met 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-val197ala (accessed [today's date]).

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