Is CRYBA4 p.Phe29Ile (c.85T>A) pathogenic?

CRYBA4 p.Phe29Ile (c.85T>A) is classified Uncertain significance in CRYBA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-06). AlphaMissense: ambiguous (0.5117); Ultra-rare (popmax 0.0388%, afr); Associated with Inborn genetic diseases.

What condition is associated with CRYBA4 p.Phe29Ile (c.85T>A)?

CRYBA4 p.Phe29Ile (c.85T>A) is associated with Inborn genetic diseases (ClinVar).

How common is CRYBA4 p.Phe29Ile (c.85T>A) in the general population?

CRYBA4 p.Phe29Ile (c.85T>A) is ultra-rare (popmax 0.0388%, afr) (gnomAD).

What do computational predictors say about CRYBA4 p.Phe29Ile (c.85T>A)?

AlphaMissense predicts ambiguous (score 0.5117) — an in-silico prediction, not a clinical call.

CRYBA4 p.Phe29Ile

c.85T>A · rs149551651 · VCV2371567

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5117 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0388%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5117	ambiguous
REVEL	0.548	indeterminate
SaProt	LLR -9.18	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 7,887 bp · p 0.027 · regional, not allelic
Overall
CADD	22.7	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 0.0388% African / African-American · 29/74,832 alleles

Filtering AF 0.0277% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0239%

Overall 0.00198% 32/1,613,696 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0388%	2,580
Remaining individualsnot grpmax-eligible	0.0048%	20,829

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.Phe29Ile
Coding: c.85T>A
MANE Select: NM_001886
dbSNP: rs149551651
Type: single nucleotide variant
Location: chr22:26623279 (GRCh38)
Gene constraint: LOEUF 1.238 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.64 · 1 PDB
Residue 29: a β-strand; the beta/gamma crystallin 'greek key' 1 domain

Full CRYBA4 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

CRYBA4 p.Phe29Leu Uncertain significance ★★ ⚠ same residue
CRYBA4 p.Ile109Val Uncertain significance ★★ ⚠ same condition
CRYBB1 p.Ala98Glu Uncertain significance ★★ ⚠ same condition
CRYBB1 p.Arg132Cys Uncertain significance ★★ ⚠ same condition
CRYBB1 p.Arg231His Uncertain significance ★★ ⚠ same condition
CRYBB1 p.Lys150Glu Uncertain significance ★★ ⚠ same condition
CRYBB1 p.Ser130Thr Uncertain significance ★★ ⚠ same condition
CRYBB1 p.Trp193Cys 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/cryba4-p-phe29ile (accessed [today's date]).

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