Is CRY1 p.Pro193Ser (c.577C>T) pathogenic?

CRY1 p.Pro193Ser (c.577C>T) is classified Uncertain significance in CRY1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-01). AlphaMissense: likely pathogenic (0.9944); Absent from gnomAD v4.1.

How common is CRY1 p.Pro193Ser (c.577C>T) in the general population?

CRY1 p.Pro193Ser (c.577C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CRY1 p.Pro193Ser (c.577C>T)?

AlphaMissense predicts likely pathogenic (score 0.9944) — an in-silico prediction, not a clinical call.

CRY1 p.Pro193Ser

c.577C>T · rs2499974648 · VCV2331417

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9944 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9944	likely pathogenic
REVEL	0.501	indeterminate
SaProt	LLR -13.35	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 100 kb · p 1.3e-06 · regional, not allelic
Overall
CADD	28.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CRY1
Protein: p.Pro193Ser
Coding: c.577C>T
MANE Select: NM_004075
dbSNP: rs2499974648
Type: single nucleotide variant
Location: chr12:107001782 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.32

Full CRY1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CRY1 p.Arg256Gln Uncertain significance ★★ ⚠ same type
CRY1 p.Thr179Ala Uncertain significance ★★ ⚠ same type
CRY1 p.Ala331= Benign ★★ same type
CRY1 p.Ala501= Benign ★★ same type
CRY1 p.Ala111Thr Uncertain significance ★ ⚠ same type
CRY1 p.Ala241Val Uncertain significance ★ ⚠ same type
CRY1 p.Ala331Gly Uncertain significance ★ same type
CRY1 p.Ala5Gly 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/cry1-p-pro193ser (accessed [today's date]).

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