Is CRYGC p.Cys42Arg (c.124T>C) pathogenic?

CRYGC p.Cys42Arg (c.124T>C) is classified Uncertain significance in CRYGC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-13). AlphaMissense: likely pathogenic (0.7199); Ultra-rare (popmax 0.0493%, mid); Associated with Inborn genetic diseases.

What condition is associated with CRYGC p.Cys42Arg (c.124T>C)?

CRYGC p.Cys42Arg (c.124T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CRYGC p.Cys42Arg (c.124T>C) in the general population?

CRYGC p.Cys42Arg (c.124T>C) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

What do computational predictors say about CRYGC p.Cys42Arg (c.124T>C)?

AlphaMissense predicts likely pathogenic (score 0.7199) — an in-silico prediction, not a clinical call.

CRYGC p.Cys42Arg

c.124T>C · rs200511472 · VCV3077899

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7199 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7199	likely pathogenic
REVEL	0.677	pathogenic-leaning
SaProt	LLR -12.37	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 6.5	GERP 2.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 1,586 bp · p 0.96 · regional, not allelic
Overall
CADD	24.2	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

Grpmax group 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00715%

Overall 0.00198% 32/1,614,130 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.054%	1,851
Middle Easterngrpmax	0.0493%	2,028
African / African-American	0.00267%	37,469
Admixed American	0.00167%	60,010
Remaining individualsnot grpmax-eligible	0.0016%	62,490
South Asian	0.0011%	91,092
European (non-Finnish)	0.000678%	147,506

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Cys42Arg
Coding: c.124T>C
MANE Select: NM_020989
dbSNP: rs200511472
Type: single nucleotide variant
Location: chr2:208129569 (GRCh38)
Gene constraint: LOEUF 0.941 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 96.66 · 1 PDB
Residue 42: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CRYGC p.Cys42Tyr Uncertain significance ★ ⚠ same residue
CRYGC p.Arg77His Uncertain significance ★★ ⚠ same condition
CRYGC p.Asn138Ser Uncertain significance ★★ ⚠ same condition
CRYGC p.Met160Thr Uncertain significance ★★ ⚠ same condition
CRYGC p.Ala164Val Uncertain significance ★ ⚠ same condition
CRYGC p.Arg115Cys Uncertain significance ★ ⚠ same condition
CRYGC p.Arg115His Uncertain significance ★ ⚠ same condition
CRYGC p.Arg147Lys 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-cys42arg (accessed [today's date]).

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