Is CRYGD p.Leu45Pro (c.134T>C) pathogenic?

CRYGD p.Leu45Pro (c.134T>C) is classified Likely pathogenic in CRYGD (ClinVar, Single submitter, 2 submitters). AlphaMissense: likely pathogenic (0.9117); Absent from gnomAD v4.1.

How common is CRYGD p.Leu45Pro (c.134T>C) in the general population?

CRYGD p.Leu45Pro (c.134T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CRYGD p.Leu45Pro (c.134T>C)?

AlphaMissense predicts likely pathogenic (score 0.9117) — an in-silico prediction, not a clinical call.

CRYGD p.Leu45Pro

c.134T>C · rs786205546 · VCV191146

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9117 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9117	likely pathogenic ✓ concordant with ClinVar · top 6% in CRYGD
REVEL	0.801	moderately pathogenic-leaning
SaProt	LLR -11.61	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,797 bp · p 0.94 · regional, not allelic
Overall
CADD	25.1	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

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: CRYGD
Protein: p.Leu45Pro
Coding: c.134T>C
MANE Select: NM_006891
dbSNP: rs786205546
Type: single nucleotide variant
Location: chr2:208124230 (GRCh38)
Gene constraint: LOEUF 1.796 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.45 · 16 PDB
Residue 45: a UniProt-annotated variant site (in ctrct4; uncertain significance); a β-strand; the beta/gamma crystallin 'greek key' 2 domain

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

Similar variants

CRYGD p.Arg140Ter Pathogenic ★★ same type
CRYGD p.Arg15Cys Pathogenic ★★ ⚠ same type
CRYGD p.Arg37Pro Likely pathogenic ★★ same type
CRYGD p.Pro24Thr Pathogenic/Likely pathogenic ★★ ⚠ same type
CRYGD p.Trp157Ter Pathogenic/Likely pathogenic ★★ same type
CRYGD p.Arg115His Uncertain significance ★★ ⚠ same type
CRYGD p.Arg140Gln Uncertain significance ★★ ⚠ same type
CRYGD p.Asn119Ser 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/crygd-p-leu45pro (accessed [today's date]).

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