Is CTRB1 p.Val85Met (c.253G>A) pathogenic?

CTRB1 p.Val85Met (c.253G>A) is classified Uncertain significance in CTRB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-25). AlphaMissense: ambiguous (0.3994); Very rare (popmax 0.00461%, amr).

How common is CTRB1 p.Val85Met (c.253G>A) in the general population?

CTRB1 p.Val85Met (c.253G>A) is very rare (popmax 0.00461%, amr) (gnomAD).

What do computational predictors say about CTRB1 p.Val85Met (c.253G>A)?

AlphaMissense predicts ambiguous (score 0.3994) — an in-silico prediction, not a clinical call.

CTRB1 p.Val85Met

c.253G>A · rs1475879220 · VCV2468621

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3994 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00461%, amr)

Computational evidence

Protein change
AlphaMissense	0.3994	ambiguous
REVEL	0.365	indeterminate
SaProt	LLR -10.15	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -0.41, phastCons 0.45
Regional constraint	o/e 0.13	constrained · MANE · 1,089 bp · p 5.9e-17 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00461% Admixed American · 2/43,340 alleles

Filtering AF 0.00218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00276% 30/1,088,256 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00461%	21,670
African / African-American	0.00343%	29,158
European (non-Finnish)	0.00322%	31,085
Remaining individualsnot grpmax-eligible	0.00221%	45,346
South Asian	0.00135%	73,872

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.Val85Met
Coding: c.253G>A
MANE Select: NM_001906
dbSNP: rs1475879220
Type: single nucleotide variant
Location: chr16:75223157 (GRCh38)
Gene constraint: LOEUF 1.902 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.90
Residue 85: 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.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
CTRB1 p.Arg131Cys 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-val85met (accessed [today's date]).

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