# NM_015375.3(DSTYK):c.2028C>T (p.Phe676=)

https://sugi.bio/variant/dstyk-p-phe676

## Summary

**DSTYK p.Phe676= (c.2028C>T)** is classified **Benign** in DSTYK (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). Common (popmax 40.7%, sas) — too common for a highly-penetrant pathogenic allele; Associated with hereditary spastic paraplegia 23.

**At a glance:** Benign · review: Multiple submitters · rsID rs1062715 · 6 submitters · 2 linked conditions · common (popmax 40.7%, sas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the DSTYK gene that is classified as benign — not considered disease-causing, submitted by 6 submitters, and is linked to hereditary spastic paraplegia 23.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood |
| Diagnostic panels | DSTYK is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Autosomal recessive spastic paraplegia type 23** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Multiple lentigines — Frequent (79-30%)
- Vitiligo — Frequent (79-30%)
- Spastic paraplegia — Frequent (79-30%)
- Hyperreflexia — Frequent (79-30%)
- Spastic gait — Frequent (79-30%)
- Waddling gait — Frequent (79-30%)
- Bowel incontinence — Frequent (79-30%)
- Kyphoscoliosis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000336/index) · [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.Phe676= |
| Coding change (HGVS c.) | c.2028C>T |
| MANE Select transcript | [NM_015375](https://www.ncbi.nlm.nih.gov/nuccore/NM_015375) |
| dbSNP | [rs1062715](https://www.ncbi.nlm.nih.gov/snp/rs1062715/) |
| Variant type | single nucleotide variant |
| Location | chr1:205160191-205160191 (GRCh38) |
| ClinVar | [VCV260658](https://www.ncbi.nlm.nih.gov/clinvar/variation/260658/) |

**All HGVS expressions:** `NC_000001.10:g.205129319G>A`, `NC_000001.11:g.205160191G>A`, `NG_033904.1:g.56409C>T`, `NM_015375.3:c.2028C>T`, `NM_199462.3:c.2028C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 40.7%, sas) — too common for a highly-penetrant pathogenic allele.

- **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 2.601, GERP 0.649, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 8.186**. 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** — 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 (gnomAD v4.1): grpmax **40.7%** (sas) · FAF95 40.3% · FAF99 40.2% · 37,043/91,068 in the highest group · 427,240/1,613,754 alleles overall — common (popmax 40.7%, sas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 40.7% | 2 |
| East Asian | 40.5% | 2 |
| African / African-American | 37.6% | 3 |
| Admixed American | 33.4% | 3 |
| Amish (not grpmax-eligible) | 31.2% | 3 |
| Finnish (not grpmax-eligible) | 31.1% | 3 |
| Ashkenazi Jewish (not grpmax-eligible) | 28.9% | 3 |
| Remaining individuals (not grpmax-eligible) | 27.8% | 4 |
| Middle Eastern | 24.1% | 4 |
| European (non-Finnish) | 23.4% | 4 |

*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 **676** lies in the protein kinase domain; 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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-03.

**Submitter consensus:** unanimous (7/7 Benign).

**Submission history:** 7 submissions (2020–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-07-30 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-03 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-26 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2020-02-13 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

[hereditary spastic paraplegia 23](https://sugi.bio/atlas/disease/hereditary-spastic-paraplegia-23/), [congenital anomalies of kidney and urinary tract 1](https://sugi.bio/atlas/disease/congenital-anomalies-of-kidney-and-urinary-tract-1/).

**Reported phenotype names (ClinVar):** Hereditary spastic paraplegia 23, not specified, not provided, Congenital anomalies of kidney and urinary tract 1, LISON SYNDROME, SPASTIC PARAPARESIS, VITILIGO, PREMATURE GRAYING, CHARACTERISTIC FACIES, SPASTIC PARAPLEGIA WITH PIGMENTARY ABNORMALITIES, Renal hypodysplasia, nonsyndromic, 1, Congenital anomalies of kidney and urinary tract 1, susceptibility to, none provided.

## Similar variants {#similar}

Related DSTYK variant pages (same residue, condition, or type): [DSTYK p.Arg626Gln](/variant/dstyk-p-arg626gln), [DSTYK p.Gly32Asp](/variant/dstyk-p-gly32asp), [DSTYK p.His203Gln](/variant/dstyk-p-his203gln), [DSTYK p.Cys641Arg](/variant/dstyk-p-cys641arg), [DSTYK p.Gln465Arg](/variant/dstyk-p-gln465arg), [DSTYK p.Gly493Ter](/variant/dstyk-p-gly493ter), [DSTYK c.1819-18T>A](/variant/dstyk-c-1819-minus-18t-a), [DSTYK c.1819-3C>T](/variant/dstyk-c-1819-minus-3c-t).

### 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 260658). 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.*