# NM_001289808.2(CRYAB):c.343del (p.Ser115fs)

https://sugi.bio/variant/cryab-p-ser115fs

## Summary

**CRYAB p.Ser115fs (c.343del)** is classified **Conflicting classifications of pathogenicity** in CRYAB (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-01). Very rare (popmax 0.00401%, afr); Associated with Cardiovascular phenotype.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs281865142 · 7 submitters · 5 linked conditions · very rare (popmax 0.00401%, afr)

## For patients & families {#patients}

This is a change in the CRYAB gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 7 submitters, and is linked to Cardiovascular phenotype.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CRYAB](https://sugi.bio/atlas/gene/CRYAB/) |
| Protein change (HGVS p.) | p.Ser115fs |
| Coding change (HGVS c.) | c.343del |
| MANE Select transcript | [NM_001289808](https://www.ncbi.nlm.nih.gov/nuccore/NM_001289808) |
| dbSNP | [rs281865142](https://www.ncbi.nlm.nih.gov/snp/rs281865142/) |
| Variant type | Deletion |
| Location | chr11:111908949-111908949 (GRCh38) |
| ClinVar | [VCV38963](https://www.ncbi.nlm.nih.gov/clinvar/variation/38963/) |

**All HGVS expressions:** `LRG_407:g.19774del`, `LRG_407t1:c.343del`, `LRG_407t2:c.343del`, `NC_000011.10:g.111908949del`, `NC_000011.9:g.111779673del`, `NG_009824.3:g.19774del`, `NG_033080.2:g.1214del`, `NM_001289807.1:c.343del`, `NM_001289808.2:c.343del`, `NM_001330379.1:c.142del`, `NM_001368245.1:c.343del`, `NM_001368246.1:c.142del`, `NM_001885.1:c.343delT`, `NM_001885.2:c.343del`, `NM_001885.3:c.343del`

## 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 11.759, GERP 2.33, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.18, pLI 0.005468. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (3 of 3)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 34.0**. 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.
- Population frequency (gnomAD v4.1): grpmax **0.00401%** (afr) · FAF95 0.00106% · FAF99 0.000495% · 3/74,880 in the highest group · 16/1,613,966 alleles overall — very rare (popmax 0.00401%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00401% | 24,960 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,240 |
| European (non-Finnish) | 0.000932% | 107,275 |

*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}

**CRYAB** population constraint: LOEUF 1.18, pLI 0.005468, missense-Z 1.1939. *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 **115** lies in the shsp domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 75.42, 39% of residues very-high.

**21 experimental structure(s)** (PDB): [2KLR](https://www.rcsb.org/structure/2KLR), [2N0K](https://www.rcsb.org/structure/2N0K), [2WJ7](https://www.rcsb.org/structure/2WJ7), [2Y1Y](https://www.rcsb.org/structure/2Y1Y), [2Y1Z](https://www.rcsb.org/structure/2Y1Z), [2Y22](https://www.rcsb.org/structure/2Y22) — incl. mutant structure 3SGP.

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

*Describes the biological roles of CRYAB (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:** CRYAB's established molecular role includes amyloid-beta binding. p.Ser115fs falls in the shsp domain.


### Pathways affected {#pathways}

CRYAB participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [HSF1-dependent transactivation](https://reactome.org/content/detail/R-HSA-3371571) | curated |

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

**Molecular function:** amyloid-beta binding, structural molecule activity, identical protein binding, protein homodimerization activity, protein-containing complex binding, obsolete unfolded protein binding.

**Biological process:** negative regulation of protein-containing complex assembly, negative regulation of intracellular transport, negative regulation of apoptotic process, regulation of programmed cell death, negative regulation of DNA-templated transcription, protein stabilization.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-01.

**Submitter consensus:** conflicting (4 Pathogenic, 1 Uncertain significance, 1 not provided, 1 Likely pathogenic).

**Submission history:** 7 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2021-08-27 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2021-09-09 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-11 |
| GeneReviews | not provided | no classification provided | literature only |  |
| Eurofins Ntd Llc (ga) | Likely pathogenic | criteria provided, single submitter | clinical testing | 2018-08-08 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2023-02-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-02-01 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [myofibrillar myopathy 2](https://sugi.bio/atlas/disease/myofibrillar-myopathy-2/), [cataract 16 multiple types](https://sugi.bio/atlas/disease/cataract-16-multiple-types/), [fatal infantile hypertonic myofibrillar myopathy](https://sugi.bio/atlas/disease/fatal-infantile-hypertonic-myofibrillar-myopathy/), [dilated cardiomyopathy 1II](https://sugi.bio/atlas/disease/dilated-cardiomyopathy-1ii/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, Myofibrillar myopathy 2, not provided, Dilated cardiomyopathy 1II, Cataract 16 multiple types, Fatal infantile hypertonic myofibrillar myopathy, MYOPATHY, DESMIN-RELATED, ASSOCIATED WITH MUTATION IN THE CRYAB GENE, MYOPATHY, MYOFIBRILLAR, ALPHA-B CRYSTALLIN-RELATED, MYOPATHY, MYOFIBRILLAR, WITH OR WITHOUT CATARACT AND/OR CARDIOMYOPATHY, MYOPATHY, MYOFIBRILLAR, 2A, ADULT-ONSET.

## Similar variants {#similar}

Related CRYAB variant pages (same residue, condition, or type): [CRYAB p.Ser115=](/variant/cryab-p-ser115), [CRYAB p.Lys82_His83delinsAsn](/variant/cryab-p-lys82-his83delinsasn), [CRYAB p.Ala172fs](/variant/cryab-p-ala172fs), [CRYAB p.Arg11fs](/variant/cryab-p-arg11fs), [CRYAB p.Leu49fs](/variant/cryab-p-leu49fs), [CRYAB p.Ser21fs](/variant/cryab-p-ser21fs), [CRYAB p.Ala126fs](/variant/cryab-p-ala126fs), [CRYAB p.Arg50_Phe54del](/variant/cryab-p-arg50-phe54del).

### 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 38963). 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.*