Is CRYBB2 p.Ser14Thr (c.40T>A) pathogenic?

CRYBB2 p.Ser14Thr (c.40T>A) is classified Benign in CRYBB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-06). AlphaMissense: likely benign (0.0633); Common (popmax 6.96%, eas) — too common for a highly-penetrant pathogenic allele; Associated with cataract 3 multiple types.

What condition is associated with CRYBB2 p.Ser14Thr (c.40T>A)?

CRYBB2 p.Ser14Thr (c.40T>A) is associated with cataract 3 multiple types (ClinVar).

What do computational predictors say about CRYBB2 p.Ser14Thr (c.40T>A)?

AlphaMissense predicts likely benign (score 0.0633) — an in-silico prediction, not a clinical call.

CRYBB2 p.Ser14Thr

Q: How common is CRYBB2 p.Ser14Thr (c.40T>A) in the general population?

CRYBB2 p.Ser14Thr (c.40T>A) is common (popmax 6.96%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.40T>A · rs117457580 · VCV667923

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0633 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.96%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 3 multiple types

Computational evidence

Protein change
AlphaMissense	0.0633	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -5.91	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 0.77	GERP -3.1, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 10 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	14.21	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 6.96% East Asian · 3,124/44,858 alleles

Filtering AF 6.76% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.68%

Overall 0.22% 3,552/1,613,458 alleles · common exomes 3,101/1,461,202 · genomes 451/152,256 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	6.96%	14
Remaining individualsnot grpmax-eligible	0.31%	322
South Asian	0.0988%	1,012
Middle Eastern	0.0825%	1,212
Admixed American	0.0483%	2,069
African / African-American	0.04%	2,500
European (non-Finnish)	0.00661%	15,121
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
Finnishnot grpmax-eligible	0.00156%	64,030

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.Ser14Thr
Coding: c.40T>A
MANE Select: NM_000496
dbSNP: rs117457580
Type: single nucleotide variant
Location: chr22:25221469 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI 0.09 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 89.05 · 3 PDB
Residue 14: the 'n-terminal arm' region

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-ser14thr (accessed [today's date]).

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