Is CRYBB2 p.Val187Met (c.559G>A) pathogenic?

CRYBB2 p.Val187Met (c.559G>A) is classified Conflicting classifications of pathogenicity in CRYBB2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.3161); Rare (popmax 0.347%, afr); Associated with CRYBB2-related disorder.

What condition is associated with CRYBB2 p.Val187Met (c.559G>A)?

CRYBB2 p.Val187Met (c.559G>A) is associated with CRYBB2-related disorder, cataract 3 multiple types (ClinVar).

How common is CRYBB2 p.Val187Met (c.559G>A) in the general population?

CRYBB2 p.Val187Met (c.559G>A) is rare (popmax 0.347%, afr) (gnomAD).

What do computational predictors say about CRYBB2 p.Val187Met (c.559G>A)?

AlphaMissense predicts likely benign (score 0.3161) — an in-silico prediction, not a clinical call.

CRYBB2 p.Val187Met

c.559G>A · rs143080187 · VCV1039314

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.3161 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.347%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

CRYBB2-related disorder

Computational evidence

Protein change
AlphaMissense	0.3161	likely benign
REVEL	0.607	indeterminate
SaProt	LLR -8.94	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP -1.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 10 kb · p 1.7e-05 · regional, not allelic
Overall
CADD	24.3	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 0.347% African / African-American · 260/74,996 alleles

Filtering AF 0.312% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.299%

Overall 0.0189% 305/1,614,084 alleles · rare exomes 172/1,461,874 · genomes 133/152,210 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.347%	288
Remaining individualsnot grpmax-eligible	0.0256%	3,907
Middle Eastern	0.0165%	6,062
Admixed American	0.015%	6,668
South Asian	0.00659%	15,180
East Asian	0.00223%	44,868
European (non-Finnish)	0.00102%	98,334

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.Val187Met
Coding: c.559G>A
MANE Select: NM_000496
dbSNP: rs143080187
Type: single nucleotide variant
Location: chr22:25231713 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI 0.09 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 89.05 · 3 PDB
Residue 187: a UniProt-annotated variant site (in ctrct3); a β-strand; the beta/gamma crystallin 'greek key' 4 domain

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

Disease context

CRYBB2-related disorder

Also linked: cataract 3 multiple types

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 c.173+5G>A Uncertain significance ★★ same condition
CRYBB2 p.Arg160Pro Uncertain significance ★★ ⚠ same condition
CRYBB2 p.Gln183Ter Uncertain significance ★★ same condition
CRYBB2 p.Gly57Glu 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-val187met (accessed [today's date]).

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