Is CRYBB1 p.Ala146Val (c.437C>T) pathogenic?

CRYBB1 p.Ala146Val (c.437C>T) is classified Uncertain significance in CRYBB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-07). AlphaMissense: likely benign (0.0957); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

What condition is associated with CRYBB1 p.Ala146Val (c.437C>T)?

CRYBB1 p.Ala146Val (c.437C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CRYBB1 p.Ala146Val (c.437C>T) in the general population?

CRYBB1 p.Ala146Val (c.437C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CRYBB1 p.Ala146Val (c.437C>T)?

AlphaMissense predicts likely benign (score 0.0957) — an in-silico prediction, not a clinical call.

CRYBB1 p.Ala146Val

c.437C>T · VCV3836566

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0957 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.0957	likely benign
REVEL	0.191	benign-leaning
SaProt	LLR -1.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5.5	phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 17 kb · p 0.0069 · regional, not allelic
Overall
CADD	19.62	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 0.00446% East Asian · 2/44,876 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000372% 6/1,613,552 alleles · very rare exomes 5/1,461,432 · genomes 1/152,120 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,438
Remaining individualsnot grpmax-eligible	0.0032%	31,232
European (non-Finnish)	0.00017%	589,943

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: CRYBB1
Protein: p.Ala146Val
Coding: c.437C>T
MANE Select: NM_001887
Type: single nucleotide variant
Location: chr22:26602017 (GRCh38)

Full CRYBB1 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

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/crybb1-p-ala146val (accessed [today's date]).

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