Is CRY2 p.Arg561His (c.1682G>A) pathogenic?

CRY2 p.Arg561His (c.1682G>A) is classified Uncertain significance in CRY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-30). AlphaMissense: likely benign (0.1668); Very rare (popmax 0.00267%, afr).

How common is CRY2 p.Arg561His (c.1682G>A) in the general population?

CRY2 p.Arg561His (c.1682G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CRY2 p.Arg561His (c.1682G>A)?

AlphaMissense predicts likely benign (score 0.1668) — an in-silico prediction, not a clinical call.

CRY2 p.Arg561His

c.1682G>A · VCV4007126

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1668 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1668	likely benign
REVEL	0.204	benign-leaning
SaProt	LLR -9.09	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 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 2,063 bp · p 0.0054 · regional, not allelic
Overall
CADD	32.0	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 0.00267% African / African-American · 2/75,032 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00186% 30/1,614,090 alleles · very rare exomes 28/1,461,826 · genomes 2/152,264 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,516
East Asian	0.00223%	44,870
European (non-Finnish)	0.00203%	49,166
Remaining individualsnot grpmax-eligible	0.0016%	62,496
Finnishnot grpmax-eligible	0.00156%	64,028
South Asian	0.0011%	91,076

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.Arg561His
Coding: c.1682G>A
MANE Select: NM_021117
Type: single nucleotide variant
Location: chr11:45872131 (GRCh38)
Gene constraint: LOEUF 0.596 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 85.42
Residue 561: the 'disordered' region

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-arg561his (accessed [today's date]).

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