Is CRIPT p.Pro16Ala (c.46C>G) pathogenic?

CRIPT p.Pro16Ala (c.46C>G) is classified Uncertain significance in CRIPT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-19). AlphaMissense: likely pathogenic (0.8288); Very rare (popmax 0.00846%, amr).

How common is CRIPT p.Pro16Ala (c.46C>G) in the general population?

CRIPT p.Pro16Ala (c.46C>G) is very rare (popmax 0.00846%, amr) (gnomAD).

What do computational predictors say about CRIPT p.Pro16Ala (c.46C>G)?

AlphaMissense predicts likely pathogenic (score 0.8288) — an in-silico prediction, not a clinical call.

CRIPT p.Pro16Ala

c.46C>G · rs1268522123 · VCV2095880

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8288 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00846%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8288	likely pathogenic
REVEL	0.734	pathogenic-leaning
SaProt	LLR -12.64	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 6,941 bp · p 0.1 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00846% Admixed American · 5/59,108 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00389%

Overall 0.00436% 70/1,607,114 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00846%	11,822
European (non-Finnish)	0.00536%	18,669
East Asian	0.00224%	44,594
Remaining individualsnot grpmax-eligible	0.00161%	62,216

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.Pro16Ala
Coding: c.46C>G
MANE Select: NM_014171
dbSNP: rs1268522123
Type: single nucleotide variant
Location: chr2:46618802 (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

Similar variants

CRIPT c.83-1G>A Likely pathogenic ★★ same type
CRIPT p.Ala45Pro Uncertain significance ★★ ⚠ same type
CRIPT p.Ala84Val Uncertain significance ★★ ⚠ same type
CRIPT p.Cys86Phe Uncertain significance ★★ ⚠ same type
CRIPT p.Gln74Arg Uncertain significance ★★ ⚠ same type
CRIPT p.Gly81Val Uncertain significance ★★ ⚠ same type
CRIPT p.Lys88Arg Uncertain significance ★★ ⚠ same type
CRIPT p.Ser64Phe 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/cript-p-pro16ala (accessed [today's date]).

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