Is CRYBB3 p.Glu44Lys (c.130G>A) pathogenic?

CRYBB3 p.Glu44Lys (c.130G>A) is classified Uncertain significance in CRYBB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-29). AlphaMissense: likely benign (0.2575); Ultra-rare (popmax 0.016%, afr); Associated with Inborn genetic diseases.

What condition is associated with CRYBB3 p.Glu44Lys (c.130G>A)?

CRYBB3 p.Glu44Lys (c.130G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CRYBB3 p.Glu44Lys (c.130G>A) in the general population?

CRYBB3 p.Glu44Lys (c.130G>A) is ultra-rare (popmax 0.016%, afr) (gnomAD).

What do computational predictors say about CRYBB3 p.Glu44Lys (c.130G>A)?

AlphaMissense predicts likely benign (score 0.2575) — an in-silico prediction, not a clinical call.

CRYBB3 p.Glu44Lys

c.130G>A · VCV3836571

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2575 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2575	likely benign
REVEL	0.718	pathogenic-leaning
SaProt	LLR -11.85	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.5	GERP -0.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 5,812 bp · p 0.93 · regional, not allelic
Overall
CADD	27.5	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 0.016% African / African-American · 12/74,920 alleles

Filtering AF 0.00921% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.00341% 55/1,613,960 alleles · ultra-rare exomes 45/1,461,786 · genomes 10/152,174 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,243
European (non-Finnish)	0.00339%	29,501
Remaining individualsnot grpmax-eligible	0.0032%	31,243
South Asian	0.0011%	91,052

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: CRYBB3
Protein: p.Glu44Lys
Coding: c.130G>A
MANE Select: NM_004076
Type: single nucleotide variant
Location: chr22:25202728 (GRCh38)
Gene constraint: LOEUF 1.588 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.52 · 1 PDB
Residue 44: the beta/gamma crystallin 'greek key' 1 domain

Full CRYBB3 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

CRYBB3 p.Arg127Cys Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg127His Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg152Cys Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg196His Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg75Cys Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg75Leu Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Asp110Gly Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Ala13Gly Conflicting classifications of pathogenicity ★ ⚠ 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/crybb3-p-glu44lys (accessed [today's date]).

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