Is CRYAA p.Arg112His (c.335G>A) pathogenic?

CRYAA p.Arg112His (c.335G>A) is classified Uncertain significance in CRYAA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-05-09). AlphaMissense: likely pathogenic (0.996); Absent from gnomAD v4.1; Associated with cataract 9 multiple types.

What condition is associated with CRYAA p.Arg112His (c.335G>A)?

CRYAA p.Arg112His (c.335G>A) is associated with cataract 9 multiple types (ClinVar).

How common is CRYAA p.Arg112His (c.335G>A) in the general population?

CRYAA p.Arg112His (c.335G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CRYAA p.Arg112His (c.335G>A)?

AlphaMissense predicts likely pathogenic (score 0.996) — an in-silico prediction, not a clinical call.

CRYAA p.Arg112His

c.335G>A · rs200594555 · VCV898793

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 9 multiple types

Computational evidence

Protein change
AlphaMissense	0.996	likely pathogenic · top 8% in CRYAA
REVEL	0.894	moderately pathogenic-leaning
SaProt	LLR -9.59	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.13	constrained · MANE · 3,177 bp · p 1.9e-11 · regional, not allelic
Overall
CADD	29.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CRYAA
Protein: p.Arg112His
Coding: c.335G>A
MANE Select: NM_000394
dbSNP: rs200594555
Type: single nucleotide variant
Location: chr21:43172093 (GRCh38)
Structure: AlphaFold pLDDT 74.60 · 5 PDB
Residue 112: a UniProt-annotated variant site (in ctrct9; uncertain significance); the shsp domain

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.Arg112Cys Uncertain significance ★ ⚠ same residue
CRYAA p.Arg112Gly Uncertain significance ★ same residue
CRYAA p.Arg116Cys Pathogenic ★★ same condition
CRYAA p.Arg116His Pathogenic ★★ same condition
CRYAA p.Arg12Cys Pathogenic/Likely 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

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-arg112his (accessed [today's date]).

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