Is CRYBB2 p.Pro37Ser (c.109C>T) pathogenic?

CRYBB2 p.Pro37Ser (c.109C>T) is classified Uncertain significance in CRYBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-28). AlphaMissense: likely benign (0.1054); Very rare (popmax 0.000848%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CRYBB2 p.Pro37Ser (c.109C>T)?

CRYBB2 p.Pro37Ser (c.109C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CRYBB2 p.Pro37Ser (c.109C>T) in the general population?

CRYBB2 p.Pro37Ser (c.109C>T) is very rare (popmax 0.000848%, nfe) (gnomAD).

What do computational predictors say about CRYBB2 p.Pro37Ser (c.109C>T)?

AlphaMissense predicts likely benign (score 0.1054) — an in-silico prediction, not a clinical call.

CRYBB2 p.Pro37Ser

c.109C>T · rs750776090 · VCV2491273

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1054 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000848%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1054	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	LLR -6.54	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP -2.1, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 10 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	21.1	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 0.000848% European (non-Finnish) · 10/1,179,336 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.00062% 10/1,613,430 alleles · very rare exomes 10/1,461,098 · genomes 0/152,332 · joint denominator

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.Pro37Ser
Coding: c.109C>T
MANE Select: NM_000496
dbSNP: rs750776090
Type: single nucleotide variant
Location: chr22:25224972 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI 0.09 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 89.05 · 3 PDB
Residue 37: the beta/gamma crystallin 'greek key' 1 domain

Full CRYBB2 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

Similar variants

CRYBB2 p.Ala9Val Uncertain significance ★★ ⚠ same condition
CRYBB2 p.Gly57Glu Uncertain significance ★★ ⚠ same condition
CRYBB2 p.Ala134Thr Uncertain significance ★ ⚠ same condition
CRYBB2 p.Arg189His Uncertain significance ★ ⚠ same condition
CRYBB2 p.Asn40Ser Uncertain significance ★ ⚠ same condition
CRYBB2 p.Gln105Lys Uncertain significance ★ ⚠ same condition
CRYBB2 p.Gly50Asp Uncertain significance ★ ⚠ same condition
CRYBB2 p.Gly50Val 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/crybb2-p-pro37ser (accessed [today's date]).

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