Is CRYAA p.Arg21Gln (c.62G>A) pathogenic?

CRYAA p.Arg21Gln (c.62G>A) is classified Pathogenic in CRYAA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-12-10). AlphaMissense: ambiguous (0.5031); Very rare (popmax 0.000538%, nfe); Associated with cataract 9 multiple types.

What condition is associated with CRYAA p.Arg21Gln (c.62G>A)?

CRYAA p.Arg21Gln (c.62G>A) is associated with cataract 9 multiple types (ClinVar).

How common is CRYAA p.Arg21Gln (c.62G>A) in the general population?

CRYAA p.Arg21Gln (c.62G>A) is very rare (popmax 0.000538%, nfe) (gnomAD).

What do computational predictors say about CRYAA p.Arg21Gln (c.62G>A)?

AlphaMissense predicts ambiguous (score 0.5031) — an in-silico prediction, not a clinical call.

CRYAA p.Arg21Gln

c.62G>A · rs397515626 · VCV68461

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5031 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000538%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

cataract 9 multiple types

Computational evidence

Protein change
AlphaMissense	0.5031	ambiguous
REVEL	0.868	moderately pathogenic-leaning
SaProt	LLR -9.42	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 4.7, phastCons 1
Regional constraint	o/e 0.13	constrained · MANE · 3,177 bp · p 1.9e-11 · regional, not allelic
Overall
CADD	27.8	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 0.000538% European (non-Finnish) · 4/743,430 alleles

Filtering AF 0.000126% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.5e-05%

Overall 0.000411% 4/972,414 alleles · very rare

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: CRYAA
Protein: p.Arg21Gln
Coding: c.62G>A
MANE Select: NM_000394
dbSNP: rs397515626
Type: single nucleotide variant
Location: chr21:43169161 (GRCh38)
Structure: AlphaFold pLDDT 74.60 · 5 PDB
Residue 21: a UniProt-annotated variant site (in ctrct9; uncertain significance); a UniProt-annotated variant site (in ctrct9); a UniProt-annotated variant site (in ctrct9; decreases oligomer formation); the 'required for complex formation with bfsp1 and bfsp2; during homooligomerization, mediates the association of 2 dimers to form a tetramer' region

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

Disease context

cataract 9 multiple types — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CRYAA p.Arg21Trp Pathogenic/Likely pathogenic ★★ same residue
CRYAA p.Arg116Cys Pathogenic ★★ same condition
CRYAA p.Arg116His Pathogenic ★★ same condition
CRYAA p.Arg12Cys Pathogenic/Likely pathogenic ★★ same condition
CRYAA p.Arg54Cys Pathogenic/Likely pathogenic ★★ same condition
CRYAA p.Gly98Arg Pathogenic ★★ same condition
CRYAA p.Ala155Asp Uncertain significance ★★ ⚠ same condition
CRYAA p.Arg112His 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/cryaa-p-arg21gln (accessed [today's date]).

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