Is CRYGD p.Ser75Pro (c.223T>C) pathogenic?

CRYGD p.Ser75Pro (c.223T>C) is classified Uncertain significance in CRYGD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-22). AlphaMissense: ambiguous (0.516); Absent from gnomAD v4.1; Associated with CRYGD-related disorder.

What condition is associated with CRYGD p.Ser75Pro (c.223T>C)?

CRYGD p.Ser75Pro (c.223T>C) is associated with CRYGD-related disorder (ClinVar).

How common is CRYGD p.Ser75Pro (c.223T>C) in the general population?

CRYGD p.Ser75Pro (c.223T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CRYGD p.Ser75Pro (c.223T>C)?

AlphaMissense predicts ambiguous (score 0.516) — an in-silico prediction, not a clinical call.

CRYGD p.Ser75Pro

c.223T>C · rs2469110995 · VCV2632968

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.516 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

CRYGD-related disorder

Computational evidence

Protein change
AlphaMissense	0.516	ambiguous
REVEL	0.406	indeterminate
SaProt	LLR -13.96	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.54	GERP -5, phastCons 0.006
Regional constraint	o/e 1.00	unconstrained · MANE · 2,797 bp · p 0.94 · regional, not allelic
Overall
CADD	21.6	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.Ser75Pro
Coding: c.223T>C
MANE Select: NM_006891
dbSNP: rs2469110995
Type: single nucleotide variant
Location: chr2:208124141 (GRCh38)
Gene constraint: LOEUF 1.796 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.45 · 16 PDB
Residue 75: a UniProt-annotated variant site (in ctrct4; uncertain significance); the beta/gamma crystallin 'greek key' 2 domain

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

Disease context

CRYGD-related disorder

Similar variants

CRYGD p.Arg15Cys Pathogenic ★★ ⚠ same condition
CRYGD p.Arg37Pro Likely pathogenic ★★ same condition
CRYGD p.Pro24Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
CRYGD p.Asn161Ser Uncertain significance ★★ ⚠ same condition
CRYGD p.Cys79Tyr Uncertain significance ★ ⚠ same condition
CRYGD p.Tyr7His Likely benign same condition
CRYGD p.Tyr93= Likely benign same condition
CRYGD p.Glu104fs 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/crygd-p-ser75pro (accessed [today's date]).

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