Is CRYBA4 p.Ile109Val (c.325A>G) pathogenic?

CRYBA4 p.Ile109Val (c.325A>G) is classified Uncertain significance in CRYBA4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-16). AlphaMissense: likely benign (0.0891); Very rare (popmax 0.00935%, afr); Associated with Inborn genetic diseases.

What condition is associated with CRYBA4 p.Ile109Val (c.325A>G)?

CRYBA4 p.Ile109Val (c.325A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CRYBA4 p.Ile109Val (c.325A>G) in the general population?

CRYBA4 p.Ile109Val (c.325A>G) is very rare (popmax 0.00935%, afr) (gnomAD).

What do computational predictors say about CRYBA4 p.Ile109Val (c.325A>G)?

AlphaMissense predicts likely benign (score 0.0891) — an in-silico prediction, not a clinical call.

CRYBA4 p.Ile109Val

c.325A>G · rs146659565 · VCV1328690

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0891 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00935%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0891	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	LLR -6.86	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 6.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 7,887 bp · p 0.027 · regional, not allelic
Overall
CADD	18.44	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00935% African / African-American · 7/74,856 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000682% 11/1,613,848 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00935%	10,694
Admixed American	0.00167%	59,992
European (non-Finnish)	0.000254%	393,326

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.Ile109Val
Coding: c.325A>G
MANE Select: NM_001886
dbSNP: rs146659565
Type: single nucleotide variant
Location: chr22:26628312 (GRCh38)
Gene constraint: LOEUF 1.238 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.64 · 1 PDB
Residue 109: a β-strand; the beta/gamma crystallin 'greek key' 3 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

CRYBB1 p.Phe109Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CRYBA4 p.Phe29Leu 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-ile109val (accessed [today's date]).

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