Is CTRB1 p.Val41Ile (c.121G>A) pathogenic?

CTRB1 p.Val41Ile (c.121G>A) is classified Uncertain significance in CTRB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-13). AlphaMissense: likely benign (0.0893); Rare (popmax 0.106%, eas).

How common is CTRB1 p.Val41Ile (c.121G>A) in the general population?

CTRB1 p.Val41Ile (c.121G>A) is rare (popmax 0.106%, eas) (gnomAD).

What do computational predictors say about CTRB1 p.Val41Ile (c.121G>A)?

AlphaMissense predicts likely benign (score 0.0893) — an in-silico prediction, not a clinical call.

CTRB1 p.Val41Ile

c.121G>A · rs575650101 · VCV2344919

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0893 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.106%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0893	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -7.81	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 -0.096	GERP -3.8
Regional constraint	o/e 1.03	unconstrained · MANE · 3,863 bp · p 0.82 · regional, not allelic
Overall
CADD	8.862	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 0.106% East Asian · 43/40,394 alleles

Filtering AF 0.0812% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0723%

Overall 0.0126% 193/1,533,010 alleles · rare exomes 164/1,381,234 · genomes 29/151,776 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.106%	939
Middle Eastern	0.0549%	1,821
Ashkenazi Jewishnot grpmax-eligible	0.0426%	2,350
Remaining individualsnot grpmax-eligible	0.0169%	5,910
South Asian	0.0132%	7,552
European (non-Finnish)	0.00961%	10,403
Admixed American	0.00599%	16,685
African / African-American	0.00275%	36,339

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.Val41Ile
Coding: c.121G>A
MANE Select: NM_001906
dbSNP: rs575650101
Type: single nucleotide variant
Location: chr16:75222836 (GRCh38)
Gene constraint: LOEUF 1.902 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.90
Residue 41: the peptidase s1 domain

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

Similar variants

CTRB1 p.Val41Ala 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-val41ile (accessed [today's date]).

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