# NM_000394.4(CRYAA):c.50T>C (p.Phe17Ser)

https://sugi.bio/variant/cryaa-p-phe17ser

## Summary

**CRYAA p.Phe17Ser (c.50T>C)** is classified **Uncertain significance** in CRYAA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-04). AlphaMissense: ambiguous (0.3997); No allele count reported in gnomAD v4.1 (AN 1,064,882); Associated with cataract 9 multiple types.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs148704068 · 2 submitters · 1 linked condition · AlphaMissense ambiguous · no allele count reported in gnomAD v4.1 (AN 1,064,882)

## For patients & families {#patients}

This is a change in the CRYAA gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to cataract 9 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/0015364/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CRYAA](https://sugi.bio/atlas/gene/CRYAA/) |
| Protein change (HGVS p.) | p.Phe17Ser |
| Coding change (HGVS c.) | c.50T>C |
| MANE Select transcript | [NM_000394](https://www.ncbi.nlm.nih.gov/nuccore/NM_000394) |
| dbSNP | [rs148704068](https://www.ncbi.nlm.nih.gov/snp/rs148704068/) |
| Variant type | single nucleotide variant |
| Location | chr21:43169149-43169149 (GRCh38) |
| ClinVar | [VCV2514624](https://www.ncbi.nlm.nih.gov/clinvar/variation/2514624/) |

**All HGVS expressions:** `NC_000021.8:g.44589259T>C`, `NC_000021.9:g.43169149T>C`, `NG_009823.1:g.5119T>C`, `NM_000394.4:c.50T>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.3997) — no call either way
- REVEL 0.462 (indeterminate)
- SaProt LLR -5.864 (tolerated)
- Conservation: phyloP 4.859, GERP 4.39, phastCons 1 — highly conserved
- CADD: **PHRED 24.2**. 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.*
- Regional missense constraint: **o/e 0.13** across the covering region of the MANE Select transcript (43,169,100–43,172,277), spanning 3,177 bp — the region is depleted of missense variation. Chi-square p 1.9e-11. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,064,882)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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.*

## Protein context {#protein}

Residue **17** lies in a UniProt-annotated variant site (in ctrct9; uncertain significance); the 'required for complex formation with bfsp1 and bfsp2; during homooligomerization, mediates the association of 2 dimers to form a tetramer' region.

AlphaFold model confidence (whole protein): pLDDT 74.60, 41% of residues very-high.

**5 experimental structure(s)** (PDB): [6T1R](https://www.rcsb.org/structure/6T1R), [9MTZ](https://www.rcsb.org/structure/9MTZ), [9MU0](https://www.rcsb.org/structure/9MU0), [9MYQ](https://www.rcsb.org/structure/9MYQ), [9U4L](https://www.rcsb.org/structure/9U4L) — incl. mutant structure 9MTZ.

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

*Describes the biological roles of CRYAA (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:** CRYAA's established molecular role includes structural molecule activity. p.Phe17Ser falls in the required for complex formation with bfsp1 and bfsp2; during homooligomerization, mediates the association of 2 dimers to form a tetramer region.


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

**Molecular function:** structural molecule activity, identical protein binding, obsolete unfolded protein binding.

**Biological process:** visual perception, negative regulation of intracellular transport, negative regulation of apoptotic process, protein stabilization.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-04.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-25 |

## Associated conditions {#conditions}

[cataract 9 multiple types](https://sugi.bio/atlas/disease/cataract-9-multiple-types/).

**Reported phenotype names (ClinVar):** Cataract 9 multiple types, not specified, AllHighlyPenetrant, Cataract 9, multiple types, with or without microcornea, Cataract, autosomal recessive congenital 1.

## Similar variants {#similar}

Related CRYAA variant pages (same residue, condition, or type): [CRYAA p.Arg116Cys](/variant/cryaa-p-arg116cys), [CRYAA p.Arg116His](/variant/cryaa-p-arg116his), [CRYAA p.Arg12Cys](/variant/cryaa-p-arg12cys), [CRYAA p.Arg21Gln](/variant/cryaa-p-arg21gln), [CRYAA p.Arg21Trp](/variant/cryaa-p-arg21trp), [CRYAA p.Arg54Cys](/variant/cryaa-p-arg54cys), [CRYAA p.Gly98Arg](/variant/cryaa-p-gly98arg), [CRYAA p.Ala155Asp](/variant/cryaa-p-ala155asp).

### 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 2514624). 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.*