# NM_015375.3(DSTYK):c.2747C>T (p.Ser916Phe)

https://sugi.bio/variant/dstyk-p-ser916phe

## Summary

**DSTYK p.Ser916Phe (c.2747C>T)** is classified **Likely benign** in DSTYK (ClinVar, Single submitter, 2 submitters; last evaluated 2025-11-12). AlphaMissense: likely benign (0.0871); Rare (popmax 0.237%, afr).

**At a glance:** Likely benign · review: Single submitter · rsID rs151054719 · 2 submitters · AlphaMissense likely benign · rare (popmax 0.237%, afr)

## For patients & families {#patients}

This is a change in the DSTYK gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

*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.Ser916Phe |
| Coding change (HGVS c.) | c.2747C>T |
| MANE Select transcript | [NM_015375](https://www.ncbi.nlm.nih.gov/nuccore/NM_015375) |
| dbSNP | [rs151054719](https://www.ncbi.nlm.nih.gov/snp/rs151054719/) |
| Variant type | single nucleotide variant |
| Location | chr1:205147601-205147601 (GRCh38) |
| ClinVar | [VCV2071647](https://www.ncbi.nlm.nih.gov/clinvar/variation/2071647/) |

**All HGVS expressions:** `NC_000001.10:g.205116729G>A`, `NC_000001.11:g.205147601G>A`, `NG_033904.1:g.68999C>T`, `NM_015375.2:c.2747C>T`, `NM_015375.3:c.2747C>T`, `NM_199462.3:c.2612C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0871)
- REVEL 0.185 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.507 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 4.763, GERP 1.48, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.5**. 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 1.02** across the covering region of the MANE Select transcript (205,147,561–205,147,715), spanning 154 bp. Chi-square p 0.89. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.52 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.237%** (afr) · FAF95 0.209% · FAF99 0.198% · 178/75,048 in the highest group · 206/1,613,748 alleles overall — rare (popmax 0.237%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.237% | 422 |
| Middle Eastern | 0.033% | 3,030 |
| Remaining individuals (not grpmax-eligible) | 0.0288% | 3,472 |
| Admixed American | 0.00833% | 12,002 |
| European (non-Finnish) | 0.000254% | 393,216 |

*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 **916** 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-12.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2022–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2022-08-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-12 |

**Reported phenotype names (ClinVar):** not provided, DSTYK-related disorder, DSTYK-related condition, 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 2071647). 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.*