Is CRYAA p.Phe53Leu (c.157T>C) pathogenic?

CRYAA p.Phe53Leu (c.157T>C) is classified Uncertain significance in CRYAA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely pathogenic (0.7984); Very rare (popmax 0.000573%, nfe).

How common is CRYAA p.Phe53Leu (c.157T>C) in the general population?

CRYAA p.Phe53Leu (c.157T>C) is very rare (popmax 0.000573%, nfe) (gnomAD).

What do computational predictors say about CRYAA p.Phe53Leu (c.157T>C)?

AlphaMissense predicts likely pathogenic (score 0.7984) — an in-silico prediction, not a clinical call.

CRYAA p.Phe53Leu

c.157T>C · VCV4234568

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7984 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000573%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7984	likely pathogenic
REVEL	0.382	indeterminate
SaProt	LLR -4.56	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.68, phastCons 1
Regional constraint	o/e 0.13	constrained · MANE · 3,177 bp · p 1.9e-11 · regional, not allelic
Overall
CADD	17.77	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 0.000573% European (non-Finnish) · 3/523,264 alleles

Filtering AF 0.000153% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.2e-05%

Overall 0.000407% 3/737,022 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.Phe53Leu
Coding: c.157T>C
MANE Select: NM_000394
Type: single nucleotide variant
Location: chr21:43169256 (GRCh38)
Structure: AlphaFold pLDDT 74.60 · 5 PDB
Residue 53: 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

Similar variants

CRYAA p.Phe53= Likely benign ★ same residue
CRYAA p.Arg116Cys Pathogenic ★★ same type
CRYAA p.Arg116His Pathogenic ★★ same type
CRYAA p.Arg116Ser Pathogenic ★★ same type
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

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-phe53leu (accessed [today's date]).

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