Is CRY2 p.Leu75Val (c.223C>G) pathogenic?

CRY2 p.Leu75Val (c.223C>G) is classified Uncertain significance in CRY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-03). AlphaMissense: ambiguous (0.4684); Very rare (popmax 0.00133%, afr).

How common is CRY2 p.Leu75Val (c.223C>G) in the general population?

CRY2 p.Leu75Val (c.223C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CRY2 p.Leu75Val (c.223C>G)?

AlphaMissense predicts ambiguous (score 0.4684) — an in-silico prediction, not a clinical call.

CRY2 p.Leu75Val

c.223C>G · VCV3497339

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4684 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4684	ambiguous
REVEL	0.275	benign-leaning
SaProt	LLR -11.66	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.6, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 23 kb · p 1.9e-08 · regional, not allelic
Overall
CADD	24.3	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 0.00133% African / African-American · 1/75,060 alleles

Overall 6.2e-05% 1/1,614,018 alleles · very rare exomes 1/1,461,672 · genomes 0/152,346 · 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.Leu75Val
Coding: c.223C>G
MANE Select: NM_021117
Type: single nucleotide variant
Location: chr11:45855989 (GRCh38)
Gene constraint: LOEUF 0.596 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 85.42
Residue 75: the photolyase/cryptochrome alpha/beta domain

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-leu75val (accessed [today's date]).

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