Is CRYAA p.Arg116Ser (c.346C>A) pathogenic?

CRYAA p.Arg116Ser (c.346C>A) is classified Pathogenic in CRYAA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-01). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CRYAA p.Arg116Ser (c.346C>A)?

CRYAA p.Arg116Ser (c.346C>A) is associated with Inborn genetic diseases (ClinVar).

How common is CRYAA p.Arg116Ser (c.346C>A) in the general population?

CRYAA p.Arg116Ser (c.346C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CRYAA p.Arg116Ser (c.346C>A)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

CRYAA p.Arg116Ser

c.346C>A · rs74315439 · VCV521018

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic ✓ concordant with ClinVar · top 1% in CRYAA
REVEL	0.968	strongly pathogenic-leaning
SaProt	LLR -13.29	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 5.7	GERP -0.91, phastCons 1
Regional constraint	o/e 0.13	constrained · MANE · 3,177 bp · p 1.9e-11 · regional, not allelic
Overall
CADD	29.6	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.Arg116Ser
Coding: c.346C>A
MANE Select: NM_000394
dbSNP: rs74315439
Type: single nucleotide variant
Location: chr21:43172104 (GRCh38)
Structure: AlphaFold pLDDT 74.60 · 5 PDB
Residue 116: a UniProt-annotated variant site (in ctrct9; uncertain significance); the shsp domain; a UniProt-annotated variant site (in ctrct9; zonular central nuclear cataract; reduced chaperone-like activity and increased membrane-binding capacity); a UniProt-annotated variant site (in ctrct9; reverse phase-high-performance liquid chromatography suggests an increased hydrophobicity of the mutant protein; loss of chaperone activity of the mutant is seen in dl-dithiothreitol-induced insulin aggregation assay; fast protein liquid chromatography purification shows that the mutant protein has increased binding affinity to lysozyme)

Full CRYAA 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

CRYAA p.Arg116Cys Pathogenic ★★ same residue
CRYAA p.Arg116His Pathogenic ★★ same residue
CRYAA p.Arg116Leu Likely pathogenic ★ same residue
CRYAA p.Arg12Cys Pathogenic/Likely pathogenic ★★ same type
CRYAA p.Arg21Gln Pathogenic ★★ ⚠ same type
CRYAA p.Arg21Trp Pathogenic/Likely pathogenic ★★ same type
CRYAA p.Arg54Cys Pathogenic/Likely pathogenic ★★ same type
CRYAA p.Gly98Arg Pathogenic ★★ same type

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-arg116ser (accessed [today's date]).

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