Is CRYBB3 p.Val26Met (c.76G>A) pathogenic?

CRYBB3 p.Val26Met (c.76G>A) is classified Uncertain significance in CRYBB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-16). AlphaMissense: ambiguous (0.445); Very rare (popmax 0.00666%, amr); Associated with Inborn genetic diseases.

What condition is associated with CRYBB3 p.Val26Met (c.76G>A)?

CRYBB3 p.Val26Met (c.76G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CRYBB3 p.Val26Met (c.76G>A) in the general population?

CRYBB3 p.Val26Met (c.76G>A) is very rare (popmax 0.00666%, amr) (gnomAD).

What do computational predictors say about CRYBB3 p.Val26Met (c.76G>A)?

AlphaMissense predicts ambiguous (score 0.445) — an in-silico prediction, not a clinical call.

CRYBB3 p.Val26Met

c.76G>A · VCV4234593

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.445 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.445	ambiguous
REVEL	0.422	indeterminate
SaProt	LLR -6.35	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.2	GERP -1.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 5,812 bp · p 0.93 · regional, not allelic
Overall
CADD	21.5	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 0.00666% Admixed American · 4/60,026 alleles

Filtering AF 0.00225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000274% 4/1,461,536 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: CRYBB3
Protein: p.Val26Met
Coding: c.76G>A
MANE Select: NM_004076
Type: single nucleotide variant
Location: chr22:25202674 (GRCh38)
Gene constraint: LOEUF 1.588 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.52 · 1 PDB
Residue 26: a β-strand; 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-val26met (accessed [today's date]).

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