Is CRYBB1 p.Ser130Thr (c.389G>C) pathogenic?

CRYBB1 p.Ser130Thr (c.389G>C) is classified Uncertain significance in CRYBB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-19). AlphaMissense: likely benign (0.286); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with CRYBB1 p.Ser130Thr (c.389G>C)?

CRYBB1 p.Ser130Thr (c.389G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CRYBB1 p.Ser130Thr (c.389G>C) in the general population?

CRYBB1 p.Ser130Thr (c.389G>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CRYBB1 p.Ser130Thr (c.389G>C)?

AlphaMissense predicts likely benign (score 0.286) — an in-silico prediction, not a clinical call.

CRYBB1 p.Ser130Thr

c.389G>C · rs748354975 · VCV2481284

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.286 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.286	likely benign
REVEL	0.452	indeterminate
SaProt	LLR -8.83	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5.9	phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 17 kb · p 0.0069 · regional, not allelic
Overall
CADD	24.8	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 0.0165% Middle Eastern · 1/6,062 alleles

Overall 0.000205% 3/1,461,876 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Admixed American	0.00167%	60,030
South Asian	0.0011%	91,092

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.Ser130Thr
Coding: c.389G>C
MANE Select: NM_001886 · reported on NM_001887
dbSNP: rs748354975
Type: single nucleotide variant
Location: chr22:26607932 (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-ser130thr (accessed [today's date]).

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