Is CRY2 p.Ala16Pro (c.46G>C) pathogenic?

CRY2 p.Ala16Pro (c.46G>C) is classified Uncertain significance in CRY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-30). AlphaMissense: likely benign (0.0767); Very rare (popmax 8.54e-05%, nfe).

How common is CRY2 p.Ala16Pro (c.46G>C) in the general population?

CRY2 p.Ala16Pro (c.46G>C) is very rare (popmax 8.54e-05%, nfe) (gnomAD).

What do computational predictors say about CRY2 p.Ala16Pro (c.46G>C)?

AlphaMissense predicts likely benign (score 0.0767) — an in-silico prediction, not a clinical call.

CRY2 p.Ala16Pro

c.46G>C · VCV3269643

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0767 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.54e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0767	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -7.51	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 1.4	GERP 0.64, phastCons 0.001
Regional constraint	o/e 1.26	unconstrained · MANE · 68 bp · p 0.12 · regional, not allelic
Overall
CADD	11.53	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 8.54e-05% European (non-Finnish) · 1/1,170,904 alleles

Overall 6.97e-05% 1/1,434,588 alleles · very rare

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.Ala16Pro
Coding: c.46G>C
MANE Select: NM_021117
Type: single nucleotide variant
Location: chr11:45847536 (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.Ala260Val 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-ala16pro (accessed [today's date]).

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