Is CRYAA p.Arg12His (c.35G>A) pathogenic?

CRYAA p.Arg12His (c.35G>A) is classified Uncertain significance in CRYAA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-27). AlphaMissense: likely pathogenic (0.5918); Very rare (popmax 0.00148%, nfe); Associated with cataract 9 multiple types.

What condition is associated with CRYAA p.Arg12His (c.35G>A)?

CRYAA p.Arg12His (c.35G>A) is associated with cataract 9 multiple types (ClinVar).

How common is CRYAA p.Arg12His (c.35G>A) in the general population?

CRYAA p.Arg12His (c.35G>A) is very rare (popmax 0.00148%, nfe) (gnomAD).

What do computational predictors say about CRYAA p.Arg12His (c.35G>A)?

AlphaMissense predicts likely pathogenic (score 0.5918) — an in-silico prediction, not a clinical call.

CRYAA p.Arg12His

c.35G>A · rs776884812 · VCV1372044

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5918 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00148%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 9 multiple types

Computational evidence

Protein change
AlphaMissense	0.5918	likely pathogenic
REVEL	0.838	moderately pathogenic-leaning
SaProt	LLR -8.43	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 4.4, phastCons 1
Regional constraint	o/e 0.13	constrained · MANE · 3,177 bp · p 1.9e-11 · regional, not allelic
Overall
CADD	27.2	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 0.00148% European (non-Finnish) · 11/742,376 alleles

Filtering AF 0.000795% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000581%

Overall 0.00114% 11/961,486 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.Arg12His
Coding: c.35G>A
MANE Select: NM_000394
dbSNP: rs776884812
Type: single nucleotide variant
Location: chr21:43169134 (GRCh38)
Structure: AlphaFold pLDDT 74.60 · 5 PDB
Residue 12: a UniProt-annotated variant site (in ctrct9; uncertain significance); a UniProt-annotated variant site (in ctrct9; delays hsp70 expression increase in response to heat shock); a UniProt-annotated variant site (in ctrct9; reduces protein solubility); 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.Arg12Cys Pathogenic/Likely pathogenic ★★ same residue
CRYAA p.Arg116Cys Pathogenic ★★ same condition
CRYAA p.Arg116His Pathogenic ★★ same condition
CRYAA p.Arg21Gln Pathogenic ★★ ⚠ same condition
CRYAA p.Arg21Trp 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

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-arg12his (accessed [today's date]).

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