Is CRYGC p.Arg168Trp (c.502C>T) pathogenic?

CRYGC p.Arg168Trp (c.502C>T) is classified Conflicting classifications of pathogenicity in CRYGC (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-06). AlphaMissense: ambiguous (0.4055); Low-frequency (popmax 1.09%, sas); Associated with cataract 2, multiple types.

What condition is associated with CRYGC p.Arg168Trp (c.502C>T)?

CRYGC p.Arg168Trp (c.502C>T) is associated with cataract 2, multiple types (ClinVar).

How common is CRYGC p.Arg168Trp (c.502C>T) in the general population?

CRYGC p.Arg168Trp (c.502C>T) is low-frequency (popmax 1.09%, sas) (gnomAD).

What do computational predictors say about CRYGC p.Arg168Trp (c.502C>T)?

AlphaMissense predicts ambiguous (score 0.4055) — an in-silico prediction, not a clinical call.

CRYGC p.Arg168Trp

c.502C>T · rs28931604 · VCV16945

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4055 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.09%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

cataract 2, multiple types

Computational evidence

Protein change
AlphaMissense	0.4055	ambiguous
REVEL	0.678	pathogenic-leaning
SaProt	LLR -14.90	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.022	GERP -5
Regional constraint	o/e 1.00	unconstrained · MANE · 1,586 bp · p 0.96 · regional, not allelic
Overall
CADD	21.1	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

Grpmax group 1.09% South Asian · 996/91,086 alleles

Filtering AF 1.04% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.01%

Overall 0.0671% 1,083/1,614,202 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	1.09%	91
Remaining individualsnot grpmax-eligible	0.0576%	1,736
Admixed American	0.0533%	1,876
Middle Eastern	0.0165%	6,062
African / African-American	0.00266%	37,526
European (non-Finnish)	0.00136%	73,752

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.Arg168Trp
Coding: c.502C>T
MANE Select: NM_020989
dbSNP: rs28931604
Type: single nucleotide variant
Location: chr2:208128226 (GRCh38)
Gene constraint: LOEUF 0.941 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 96.66 · 1 PDB
Residue 168: a UniProt-annotated variant site (in ctrct2; uncertain significance); a β-strand; the beta/gamma crystallin 'greek key' 4 domain

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

Disease context

cataract 2, multiple types — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CRYGC p.Arg168Gln Uncertain significance ⚠ same residue
CRYGC p.Trp157Ter Pathogenic/Likely pathogenic ★★ same condition
CRYGC p.Glu18Lys Uncertain significance ★★ ⚠ same condition
CRYGC p.Arg60Ter Likely pathogenic ★ same condition
CRYGC p.Gln113Ter Likely pathogenic ★ same condition
CRYGC p.Arg153Trp Uncertain significance ★ ⚠ same condition
CRYGC p.Asn50Ser Uncertain significance ★ ⚠ same condition
CRYGC p.Glu135Lys Uncertain significance ★ ⚠ 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-arg168trp (accessed [today's date]).

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