Is CRYGC p.Arg48Cys (c.142C>T) pathogenic?

CRYGC p.Arg48Cys (c.142C>T) is classified Uncertain significance in CRYGC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely benign (0.2424); Ultra-rare (popmax 0.0386%, afr); Associated with Nuclear pulverulent cataract.

What condition is associated with CRYGC p.Arg48Cys (c.142C>T)?

CRYGC p.Arg48Cys (c.142C>T) is associated with Nuclear pulverulent cataract (ClinVar).

How common is CRYGC p.Arg48Cys (c.142C>T) in the general population?

CRYGC p.Arg48Cys (c.142C>T) is ultra-rare (popmax 0.0386%, afr) (gnomAD).

What do computational predictors say about CRYGC p.Arg48Cys (c.142C>T)?

AlphaMissense predicts likely benign (score 0.2424) — an in-silico prediction, not a clinical call.

CRYGC p.Arg48Cys

c.142C>T · rs201568695 · VCV2080946

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2424 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0386%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Nuclear pulverulent cataract

Computational evidence

Protein change
AlphaMissense	0.2424	likely benign
REVEL	0.49	indeterminate
SaProt	LLR -9.94	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 1,586 bp · p 0.96 · regional, not allelic
Overall
CADD	29.5	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 0.0386% African / African-American · 29/75,050 alleles

Filtering AF 0.0276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0238%

Overall 0.00359% 58/1,614,204 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0386%	2,588
Admixed American	0.01%	10,004
Remaining individualsnot grpmax-eligible	0.008%	12,502
East Asian	0.00446%	22,442
South Asian	0.00329%	30,361
European (non-Finnish)	0.0011%	90,772

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: CRYGC
Protein: p.Arg48Cys
Coding: c.142C>T
MANE Select: NM_020989
dbSNP: rs201568695
Type: single nucleotide variant
Location: chr2:208129551 (GRCh38)
Gene constraint: LOEUF 0.941 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 96.66 · 1 PDB
Residue 48: a UniProt-annotated variant site (in); a β-strand; the beta/gamma crystallin 'greek key' 2 domain

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

Disease context

Nuclear pulverulent cataract — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CRYGC p.Arg48His Benign ★★ ⚠ same residue
CRYGC p.Arg122His Uncertain significance ★★ ⚠ same condition
CRYGC p.Arg15His Uncertain significance ★★ ⚠ same condition
CRYGC p.Arg77Cys Uncertain significance ★★ ⚠ same condition
CRYGC p.Glu150Asp Uncertain significance ★★ ⚠ same condition
CRYGC p.Pro49Thr Uncertain significance ★★ ⚠ same condition
CRYGC c.10-10T>C Benign/Likely benign ★★ same condition
CRYGC p.Gly41= Benign ★★ 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/crygc-p-arg48cys (accessed [today's date]).

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