# NM_015375.3(DSTYK):c.292C>G (p.Pro98Ala)

https://sugi.bio/variant/dstyk-p-pro98ala

## Summary

**DSTYK p.Pro98Ala (c.292C>G)** is classified **Uncertain significance** in DSTYK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-09). AlphaMissense: likely benign (0.0588); Ultra-rare (popmax 0.0267%, eas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0267%, eas)

## For patients & families {#patients}

This is a change in the DSTYK gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [DSTYK](https://sugi.bio/atlas/gene/DSTYK/) |
| Protein change (HGVS p.) | p.Pro98Ala |
| Coding change (HGVS c.) | c.292C>G |
| MANE Select transcript | [NM_015375](https://www.ncbi.nlm.nih.gov/nuccore/NM_015375) |
| Variant type | single nucleotide variant |
| Location | chr1:205187780-205187780 (GRCh38) |
| ClinVar | [VCV4695968](https://www.ncbi.nlm.nih.gov/clinvar/variation/4695968/) |

**All HGVS expressions:** `NC_000001.10:g.205156908G>C`, `NC_000001.11:g.205187780G>C`, `NG_033904.1:g.28820C>G`, `NM_015375.3:c.292C>G`, `NM_199462.3:c.292C>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0588)
- REVEL 0.064 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.124 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.80) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 6.482, GERP 0.326, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.7**. 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 0.77** across the covering region of the MANE Select transcript (205,157,324–205,211,294), spanning 53,970 bp. Chi-square p 2.6e-11. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.68**, donor loss **0.00**, acceptor gain **0.80**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.80**, donor gain **0.00**.
- Pangolin: Δ**0.65** (gain), gain 0.65 / loss 0.01. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0267%** (eas) · FAF95 0.0154% · FAF99 0.0121% · 12/44,886 in the highest group · 14/1,613,428 alleles overall — ultra-rare (popmax 0.0267%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0267% | 3,740 |
| Admixed American | 0.00167% | 59,928 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,460 |

*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}

**DSTYK** population constraint: LOEUF 0.445, pLI 0.99974, missense-Z 2.848. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **complex hereditary spastic paraplegia** — Moderate (AR)

## Protein context {#protein}

Residue **98** lies in a UniProt-annotated variant site (in cakut1; uncertain significance).

AlphaFold model confidence (whole protein): pLDDT 81.02, 41% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-09.

**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 | 2025-10-09 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related DSTYK variant pages (same residue, condition, or type): [DSTYK p.Ala206Val](/variant/dstyk-p-ala206val), [DSTYK p.Ala477Ser](/variant/dstyk-p-ala477ser), [DSTYK p.Ala601Val](/variant/dstyk-p-ala601val), [DSTYK p.Arg411Gln](/variant/dstyk-p-arg411gln), [DSTYK p.Arg462Gln](/variant/dstyk-p-arg462gln), [DSTYK p.Arg471Gln](/variant/dstyk-p-arg471gln), [DSTYK p.Arg626Gln](/variant/dstyk-p-arg626gln), [DSTYK p.Arg635His](/variant/dstyk-p-arg635his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 4695968). 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.*