Is CRYBB3 p.Ser42Leu (c.125C>T) pathogenic?

CRYBB3 p.Ser42Leu (c.125C>T) is classified Conflicting classifications of pathogenicity in CRYBB3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-01-28). AlphaMissense: likely benign (0.092); Rare (popmax 0.617%, afr); Associated with Inborn genetic diseases.

What condition is associated with CRYBB3 p.Ser42Leu (c.125C>T)?

CRYBB3 p.Ser42Leu (c.125C>T) is associated with Inborn genetic diseases, cataract 22 multiple types (ClinVar).

How common is CRYBB3 p.Ser42Leu (c.125C>T) in the general population?

CRYBB3 p.Ser42Leu (c.125C>T) is rare (popmax 0.617%, afr) (gnomAD).

What do computational predictors say about CRYBB3 p.Ser42Leu (c.125C>T)?

AlphaMissense predicts likely benign (score 0.092) — an in-silico prediction, not a clinical call.

CRYBB3 p.Ser42Leu

c.125C>T · rs145770544 · VCV902426

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.092 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.617%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.092	likely benign
REVEL	0.312	indeterminate
SaProt	LLR -8.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1	GERP -0.68, phastCons 0.002
Regional constraint	o/e 1.00	unconstrained · MANE · 5,812 bp · p 0.93 · regional, not allelic
Overall
CADD	20.3	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 0.617% African / African-American · 463/75,058 alleles

Filtering AF 0.57% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.552%

Overall 0.033% 532/1,614,098 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.617%	162
Admixed American	0.05%	2,001
Middle Eastern	0.0495%	2,020
Remaining individualsnot grpmax-eligible	0.0416%	2,404
Finnishnot grpmax-eligible	0.00313%	31,994
South Asian	0.0022%	45,528
European (non-Finnish)	0.000508%	196,669

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.Ser42Leu
Coding: c.125C>T
MANE Select: NM_004076
dbSNP: rs145770544
Type: single nucleotide variant
Location: chr22:25202723 (GRCh38)
Gene constraint: LOEUF 1.588 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.52 · 1 PDB
Residue 42: 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

Also linked: cataract 22 multiple types

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.Arg169Cys Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg179His Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg196His Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg207His Uncertain significance ★★ ⚠ same condition
CRYBB3 p.Arg75Cys 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/crybb3-p-ser42leu (accessed [today's date]).

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