Is CRYBA4 p.Phe57= (c.171T>C) pathogenic?

CRYBA4 p.Phe57= (c.171T>C) is classified Benign in CRYBA4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). Common (popmax 99.7%, eas) — too common for a highly-penetrant pathogenic allele; Associated with cataract 23.

What condition is associated with CRYBA4 p.Phe57= (c.171T>C)?

CRYBA4 p.Phe57= (c.171T>C) is associated with cataract 23 (ClinVar).

How is Early onset non-syndromic cataract inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CRYBA4 p.Phe57=

Q: How common is CRYBA4 p.Phe57= (c.171T>C) in the general population?

CRYBA4 p.Phe57= (c.171T>C) is common (popmax 99.7%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.171T>C · rs5761637 · VCV258487

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 99.7%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

cataract 23

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.5	GERP -3.8
Overall
CADD	1.951	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 99.7% East Asian · 44,753/44,868 alleles

Filtering AF 99% ClinGen BA1/BS1 input FAF95, joint · FAF99 98.7%

Overall 86% 1,388,106/1,613,620 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	99.7%	1
Ashkenazi Jewishnot grpmax-eligible	93.4%	1
Admixed American	92.9%	1
African / African-American	92.5%	1
South Asian	92.1%	1
Finnishnot grpmax-eligible	91.9%	1
Middle Eastern	89.5%	1
Remaining individualsnot grpmax-eligible	87.6%	1
European (non-Finnish)	83.7%	1
Amishnot grpmax-eligible	80.3%	1

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: CRYBA4
Protein: p.Phe57=
Coding: c.171T>C
MANE Select: NM_001886
dbSNP: rs5761637
Type: single nucleotide variant
Location: chr22:26625493 (GRCh38)
Gene constraint: LOEUF 1.238 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.64 · 1 PDB
Residue 57: a β-strand; the beta/gamma crystallin 'greek key' 2 domain

Full CRYBA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cataract 23 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Early onset non-syndromic cataract (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

CRYBA4 p.Phe57Val Uncertain significance ★★ ⚠ same residue
CRYBA4 p.Phe57Ile Uncertain significance ★ ⚠ same residue
CRYBA4 p.Phe57Leu Uncertain significance ★ ⚠ same residue
CRYBA4 p.Phe22Ser Uncertain significance ★★ ⚠ same condition
CRYBA4 c.159-20A>G Benign ★★ same condition
CRYBA4 c.300+3A>G Benign ★★ same condition
CRYBA4 c.40-1G>C Benign/Likely benign ★★ same condition
CRYBA4 c.444-18G>A Benign ★★ 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/cryba4-p-phe57 (accessed [today's date]).

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