Is CRYBB2 p.Ala65Ser (c.193G>T) pathogenic?

CRYBB2 p.Ala65Ser (c.193G>T) is classified Benign/Likely benign in CRYBB2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-08). AlphaMissense: likely benign (0.0825); Low-frequency (popmax 4.65%, sas); Associated with cataract 3 multiple types.

What condition is associated with CRYBB2 p.Ala65Ser (c.193G>T)?

CRYBB2 p.Ala65Ser (c.193G>T) is associated with cataract 3 multiple types (ClinVar).

How common is CRYBB2 p.Ala65Ser (c.193G>T) in the general population?

CRYBB2 p.Ala65Ser (c.193G>T) is low-frequency (popmax 4.65%, sas) (gnomAD).

What do computational predictors say about CRYBB2 p.Ala65Ser (c.193G>T)?

AlphaMissense predicts likely benign (score 0.0825) — an in-silico prediction, not a clinical call.

CRYBB2 p.Ala65Ser

c.193G>T · rs16986560 · VCV256281

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0825 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.65%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 3 multiple types

Computational evidence

Protein change
AlphaMissense	0.0825	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -6.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP -0.36, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 10 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	21.6	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 4.65% South Asian · 4,237/91,078 alleles

Filtering AF 4.54% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.49%

Overall 1.34% 21,604/1,614,088 alleles · low-frequency exomes 19,158/1,461,870 · genomes 2,446/152,218 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	4.65%	21
African / African-American	2.44%	41
Amishnot grpmax-eligible	2.42%	41
Finnishnot grpmax-eligible	2.12%	47
Remaining individualsnot grpmax-eligible	1.44%	69
European (non-Finnish)	1.06%	95
East Asian	0.773%	129
Ashkenazi Jewishnot grpmax-eligible	0.574%	174
Middle Eastern	0.544%	184
Admixed American	0.38%	263

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.Ala65Ser
Coding: c.193G>T
MANE Select: NM_000496
dbSNP: rs16986560
Type: single nucleotide variant
Location: chr22:25227872 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI 0.09 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 89.05 · 3 PDB
Residue 65: a UniProt-annotated variant site (in); a turn; the beta/gamma crystallin 'greek key' 2 domain

Full CRYBB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cataract 3 multiple types — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CRYBB2 p.Arg188Cys Pathogenic/Likely pathogenic ★★ same condition
CRYBB2 p.Arg188His Pathogenic ★★ same condition
CRYBB2 p.Gln155Ter Pathogenic/Likely pathogenic ★★ same condition
CRYBB2 p.Gly119Arg Pathogenic/Likely pathogenic ★★ same condition
CRYBB2 p.Arg160Pro Uncertain significance ★★ ⚠ same condition
CRYBB2 p.Gly57Glu Uncertain significance ★★ ⚠ same condition
CRYBB2 p.Gly61Ser Uncertain significance ★★ ⚠ same condition
CRYBB2 c.449+9G>A Benign ★★ 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-ala65ser (accessed [today's date]).

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