Is CRY2 p.Pro332Leu (c.995C>T) pathogenic?

CRY2 p.Pro332Leu (c.995C>T) is classified Uncertain significance in CRY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-28). AlphaMissense: ambiguous (0.4468); Very rare (popmax 0.00102%, nfe).

How common is CRY2 p.Pro332Leu (c.995C>T) in the general population?

CRY2 p.Pro332Leu (c.995C>T) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about CRY2 p.Pro332Leu (c.995C>T)?

AlphaMissense predicts ambiguous (score 0.4468) — an in-silico prediction, not a clinical call.

CRY2 p.Pro332Leu

c.995C>T · rs1218286651 · VCV2530561

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4468 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4468	ambiguous
REVEL	0.448	indeterminate
SaProt	LLR -13.38	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 23 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	32.0	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 0.00102% European (non-Finnish) · 12/1,180,056 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000743% 12/1,614,146 alleles · very rare exomes 11/1,461,894 · genomes 1/152,252 · 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: CRY2
Protein: p.Pro332Leu
Coding: c.995C>T
MANE Select: NM_021117
dbSNP: rs1218286651
Type: single nucleotide variant
Location: chr11:45869618 (GRCh38)
Gene constraint: LOEUF 0.596 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 85.42

Full CRY2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CRY2 p.Ala12Glu Benign ★★ same type
CRY2 p.Gly269= Benign ★★ same type
CRY2 c.37G>C Uncertain significance ★ same type
CRY2 c.-5C>T Uncertain significance ★ same type
CRY2 p.Ala12Val Uncertain significance ★ ⚠ same type
CRY2 p.Ala14Glu Uncertain significance ★ ⚠ same type
CRY2 p.Ala14Val Uncertain significance ★ ⚠ same type
CRY2 p.Ala16Pro 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/cry2-p-pro332leu (accessed [today's date]).

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