# NM_000496.3(CRYBB2):c.219del (p.Phe74fs)

https://sugi.bio/variant/crybb2-p-phe74fs

## Summary

**CRYBB2 p.Phe74fs (c.219del)** is classified **Uncertain significance** in CRYBB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-24). Very rare (popmax 0.000678%, nfe); Associated with cataract 3 multiple types.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.000678%, nfe)

## For patients & families {#patients}

This is a change in the CRYBB2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to cataract 3 multiple types.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015335/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CRYBB2](https://sugi.bio/atlas/gene/CRYBB2/) |
| Protein change (HGVS p.) | p.Phe74fs |
| Coding change (HGVS c.) | c.219del |
| MANE Select transcript | [NM_000496](https://www.ncbi.nlm.nih.gov/nuccore/NM_000496) |
| Variant type | Deletion |
| Location | chr22:25227898-25227898 (GRCh38) |
| ClinVar | [VCV3714581](https://www.ncbi.nlm.nih.gov/clinvar/variation/3714581/) |

**All HGVS expressions:** `NC_000022.10:g.25623865del`, `NC_000022.11:g.25227898del`, `NG_009827.1:g.13254del`, `NM_000496.3:c.219del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 7.818, GERP 0.762, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.765, pLI 0.089294. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 6**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 29.8**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Repeat context: **segmental_duplication** (chr22:25454748). Short reads may not map uniquely here, so both the call and its population frequency are less reliable. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- Population frequency (gnomAD v4.1): grpmax **0.000678%** (nfe) · FAF95 0.000292% · FAF99 0.000211% · 8/1,180,036 in the highest group · 8/1,614,002 alleles overall — very rare (popmax 0.000678%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CRYBB2** population constraint: LOEUF 0.765, pLI 0.089294, missense-Z 1.7421; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **74** lies in a β-strand; the beta/gamma crystallin 'greek key' 2 domain.

AlphaFold model confidence (whole protein): pLDDT 89.05, 82% of residues very-high.

**3 experimental structure(s)** (PDB): [1YTQ](https://www.rcsb.org/structure/1YTQ), [7K7U](https://www.rcsb.org/structure/7K7U), [9D1V](https://www.rcsb.org/structure/9D1V).

## What this gene does {#gene-function}

*Describes the biological roles of CRYBB2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CRYBB2's established molecular role includes identical protein binding. p.Phe74fs falls in the beta/gamma crystallin greek key 2 domain.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** identical protein binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-06-24.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-24 |

## Associated conditions {#conditions}

[cataract 3 multiple types](https://sugi.bio/atlas/disease/cataract-3-multiple-types/).

**Reported phenotype names (ClinVar):** Cataract 3 multiple types, CATARACT 3, MULTIPLE TYPES, WITH OR WITHOUT MICROCORNEA.

## Similar variants {#similar}

Related CRYBB2 variant pages (same residue, condition, or type): [CRYBB2 p.Gln155_Tyr156del](/variant/crybb2-p-gln155-tyr156del), [CRYBB2 p.Arg188Cys](/variant/crybb2-p-arg188cys), [CRYBB2 p.Arg188His](/variant/crybb2-p-arg188his), [CRYBB2 p.Gln155Ter](/variant/crybb2-p-gln155ter), [CRYBB2 p.Gly119Arg](/variant/crybb2-p-gly119arg), [CRYBB2 p.Arg160Pro](/variant/crybb2-p-arg160pro), [CRYBB2 p.Gly57Glu](/variant/crybb2-p-gly57glu), [CRYBB2 p.Gly61Ser](/variant/crybb2-p-gly61ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3714581). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*