Is CRYBB2 p.Ala9Val (c.26C>T) pathogenic?

CRYBB2 p.Ala9Val (c.26C>T) is classified Uncertain significance in CRYBB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-27). AlphaMissense: likely benign (0.0827); Ultra-rare (popmax 0.0446%, eas); Associated with Inborn genetic diseases.

What condition is associated with CRYBB2 p.Ala9Val (c.26C>T)?

CRYBB2 p.Ala9Val (c.26C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CRYBB2 p.Ala9Val (c.26C>T) in the general population?

CRYBB2 p.Ala9Val (c.26C>T) is ultra-rare (popmax 0.0446%, eas) (gnomAD).

What do computational predictors say about CRYBB2 p.Ala9Val (c.26C>T)?

AlphaMissense predicts likely benign (score 0.0827) — an in-silico prediction, not a clinical call.

CRYBB2 p.Ala9Val

c.26C>T · rs776245335 · VCV429295

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0827 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0827	likely benign
REVEL	0.176	moderately benign-leaning
SaProt	LLR -8.09	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.45	donor gain · deltas
Pangolin	Δ0.28	gain · loss 0.09 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.18	GERP 0.54, phastCons 0.91
Regional constraint	o/e 0.74	unconstrained · MANE · 10 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	22.7	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 0.0446% East Asian · 20/44,872 alleles

Filtering AF 0.0295% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0246%

Overall 0.00353% 57/1,613,728 alleles · ultra-rare exomes 51/1,461,398 · genomes 6/152,330 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0446%	2,244
Admixed American	0.00666%	15,005
Remaining individualsnot grpmax-eligible	0.0048%	20,831
African / African-American	0.004%	25,014
South Asian	0.0022%	45,538
European (non-Finnish)	0.00203%	49,151
Finnishnot grpmax-eligible	0.00156%	64,020

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: CRYBB2
Protein: p.Ala9Val
Coding: c.26C>T
MANE Select: NM_000496
dbSNP: rs776245335
Type: single nucleotide variant
Location: chr22:25221455 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI 0.09 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 89.05 · 3 PDB
Residue 9: the 'n-terminal arm' region

Full CRYBB2 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

CRYBB2 p.Ala9= Likely benign ★ same residue
CRYBB2 p.Gly57Glu Uncertain significance ★★ ⚠ same condition
CRYBB2 p.Ala134Thr Uncertain significance ★ ⚠ same condition
CRYBB2 p.Arg189His Uncertain significance ★ ⚠ same condition
CRYBB2 p.Asn40Ser Uncertain significance ★ ⚠ same condition
CRYBB2 p.Gln105Lys Uncertain significance ★ ⚠ same condition
CRYBB2 p.Gly50Asp Uncertain significance ★ ⚠ same condition
CRYBB2 p.Gly50Val 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/crybb2-p-ala9val (accessed [today's date]).

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