Is CRIPT p.Ala45Pro (c.133G>C) pathogenic?

CRIPT p.Ala45Pro (c.133G>C) is classified Uncertain significance in CRIPT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-06). AlphaMissense: likely pathogenic (0.7637); Ultra-rare (popmax 0.0168%, amr); Associated with Inborn genetic diseases.

What condition is associated with CRIPT p.Ala45Pro (c.133G>C)?

CRIPT p.Ala45Pro (c.133G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CRIPT p.Ala45Pro (c.133G>C) in the general population?

CRIPT p.Ala45Pro (c.133G>C) is ultra-rare (popmax 0.0168%, amr) (gnomAD).

What do computational predictors say about CRIPT p.Ala45Pro (c.133G>C)?

AlphaMissense predicts likely pathogenic (score 0.7637) — an in-silico prediction, not a clinical call.

CRIPT p.Ala45Pro

c.133G>C · rs759346570 · VCV2427949

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7637 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7637	likely pathogenic
REVEL	0.172	moderately benign-leaning
SaProt	LLR -7.62	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 6,941 bp · p 0.1 · regional, not allelic
Overall
CADD	25.7	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 0.0168% Admixed American · 10/59,632 alleles

Filtering AF 0.00905% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00685%

Overall 0.00103% 15/1,458,544 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0168%	5,963
European (non-Finnish)	0.000424%	235,631

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: CRIPT
Protein: p.Ala45Pro
Coding: c.133G>C
MANE Select: NM_014171
dbSNP: rs759346570
Type: single nucleotide variant
Location: chr2:46619677 (GRCh38)
Gene constraint: LOEUF 1.852 · pLI 0.19 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.77 · 1 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CRIPT p.Ala45Thr Uncertain significance ★ ⚠ same residue
CRIPT p.Ala45= Likely benign ★ same residue
CRIPT p.Ala84Val Uncertain significance ★★ ⚠ same condition
CRIPT p.Cys86Phe Uncertain significance ★★ ⚠ same condition
CRIPT p.Gln74Arg Uncertain significance ★★ ⚠ same condition
CRIPT p.Gly81Val Uncertain significance ★★ ⚠ same condition
CRIPT p.Lys88Arg Uncertain significance ★★ ⚠ same condition
CRIPT p.Ser64Phe Uncertain significance ★★ ⚠ same condition

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/cript-p-ala45pro (accessed [today's date]).

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