Is CRYGS p.Phe10Val (c.28T>G) pathogenic?

CRYGS p.Phe10Val (c.28T>G) is classified Uncertain significance in CRYGS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-09). AlphaMissense: likely pathogenic (0.7746); Absent from gnomAD v4.1; Associated with cataract 20 multiple types.

What condition is associated with CRYGS p.Phe10Val (c.28T>G)?

CRYGS p.Phe10Val (c.28T>G) is associated with cataract 20 multiple types (ClinVar).

How common is CRYGS p.Phe10Val (c.28T>G) in the general population?

CRYGS p.Phe10Val (c.28T>G) is absent from gnomAD v4.1 (gnomAD).

How is Early onset non-syndromic cataract inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CRYGS p.Phe10Val (c.28T>G)?

AlphaMissense predicts likely pathogenic (score 0.7746) — an in-silico prediction, not a clinical call.

CRYGS p.Phe10Val

c.28T>G · VCV4726229

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7746 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cataract 20 multiple types

Computational evidence

Protein change
AlphaMissense	0.7746	likely pathogenic
REVEL	0.591	indeterminate
SaProt	LLR -13.31	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 6.2	GERP 1.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 5,627 bp · p 0.1 · regional, not allelic
Overall
CADD	23.1	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: CRYGS
Protein: p.Phe10Val
Coding: c.28T>G
MANE Select: NM_017541
Type: single nucleotide variant
Location: chr3:186539591 (GRCh38)
Gene constraint: LOEUF 0.881 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 95.63 · 12 PDB
Residue 10: the beta/gamma crystallin 'greek key' 1 domain; a β-strand; a UniProt-annotated variant site (in ctrct20; uncertain significance)

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

Disease context

cataract 20 multiple types — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Early onset non-syndromic cataract (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

CRYGS p.Arg125Gln Uncertain significance ★★ ⚠ same condition
CRYGS p.Arg36His Uncertain significance ★★ ⚠ same condition
CRYGS p.Glu100Ala Uncertain significance ★★ ⚠ same condition
CRYGS p.Gly102= Benign/Likely benign ★★ same condition
CRYGS p.Gly102Glu Likely benign ★★ same condition
CRYGS p.Ile8= Benign ★★ same condition
CRYGS p.Gly18Asp Pathogenic ★ same condition
CRYGS p.Gly18Val Pathogenic ★ same condition

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/crygs-p-phe10val (accessed [today's date]).

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