Is CRYAA p.Leu52Phe (c.154C>T) pathogenic?

CRYAA p.Leu52Phe (c.154C>T) is classified Conflicting classifications of pathogenicity in CRYAA (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-31). AlphaMissense: likely benign (0.0931); Rare (popmax 0.53%, nfe); Associated with cataract 9 multiple types.

What condition is associated with CRYAA p.Leu52Phe (c.154C>T)?

CRYAA p.Leu52Phe (c.154C>T) is associated with cataract 9 multiple types (ClinVar).

How common is CRYAA p.Leu52Phe (c.154C>T) in the general population?

CRYAA p.Leu52Phe (c.154C>T) is rare (popmax 0.53%, nfe) (gnomAD).

What do computational predictors say about CRYAA p.Leu52Phe (c.154C>T)?

AlphaMissense predicts likely benign (score 0.0931) — an in-silico prediction, not a clinical call.

CRYAA p.Leu52Phe

c.154C>T · rs146914780 · VCV340096

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0931 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.53%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 9 multiple types

Computational evidence

Protein change
AlphaMissense	0.0931	likely benign
REVEL	0.28	benign-leaning
SaProt	LLR -8.15	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.13	constrained · MANE · 3,177 bp · p 1.9e-11 · regional, not allelic
Overall
CADD	18.5	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 0.53% European (non-Finnish) · 2,827/533,660 alleles

Filtering AF 0.513% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.507%

Overall 0.371% 3,061/826,052 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.53%	189
Remaining individualsnot grpmax-eligible	0.3%	333
Admixed American	0.193%	519
African / African-American	0.0752%	1,331
Ashkenazi Jewishnot grpmax-eligible	0.0248%	4,030
Finnishnot grpmax-eligible	0.017%	5,884

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.Leu52Phe
Coding: c.154C>T
MANE Select: NM_000394
dbSNP: rs146914780
Type: single nucleotide variant
Location: chr21:43169253 (GRCh38)
Structure: AlphaFold pLDDT 74.60 · 5 PDB
Residue 52: a UniProt-annotated variant site (in ctrct9; uncertain significance); the shsp domain; 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.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
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-leu52phe (accessed [today's date]).

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