Is CRYBB3 p.Arg196Cys (c.586C>T) pathogenic?

CRYBB3 p.Arg196Cys (c.586C>T) is classified Uncertain significance in CRYBB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-06). AlphaMissense: ambiguous (0.5042); Ultra-rare (popmax 0.0165%, mid).

How common is CRYBB3 p.Arg196Cys (c.586C>T) in the general population?

CRYBB3 p.Arg196Cys (c.586C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CRYBB3 p.Arg196Cys (c.586C>T)?

AlphaMissense predicts ambiguous (score 0.5042) — an in-silico prediction, not a clinical call.

CRYBB3 p.Arg196Cys

c.586C>T · VCV4857567

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5042 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5042	ambiguous
REVEL	0.796	moderately pathogenic-leaning
SaProt	LLR -10.53	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 0.64, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 5,812 bp · p 0.93 · regional, not allelic
Overall
CADD	28.8	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 0.0165% Middle Eastern · 1/6,072 alleles

Filtering AF 0.00639% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00592%

Overall 0.007% 113/1,613,558 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,072
Remaining individualsnot grpmax-eligible	0.0128%	7,810
Admixed American	0.00833%	12,000
European (non-Finnish)	0.00771%	12,967
South Asian	0.00439%	22,767
African / African-American	0.004%	24,976
East Asian	0.00223%	44,882

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.Arg196Cys
Coding: c.586C>T
MANE Select: NM_004076
Type: single nucleotide variant
Location: chr22:25207162 (GRCh38)
Gene constraint: LOEUF 1.588 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.52 · 1 PDB
Residue 196: a β-strand; the beta/gamma crystallin 'greek key' 4 domain

Full CRYBB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CRYBB3 p.Arg196His Uncertain significance ★★ ⚠ same residue
CRYBB3 p.Arg127Cys Uncertain significance ★★ ⚠ same type
CRYBB3 p.Arg127His Uncertain significance ★★ ⚠ same type
CRYBB3 p.Arg152Cys Uncertain significance ★★ ⚠ same type
CRYBB3 p.Arg169Cys Uncertain significance ★★ ⚠ same type
CRYBB3 p.Arg179His Uncertain significance ★★ ⚠ same type
CRYBB3 p.Arg207His Uncertain significance ★★ ⚠ same type
CRYBB3 p.Arg75Cys Uncertain significance ★★ ⚠ same type

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-arg196cys (accessed [today's date]).

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