Is DSTYK p.Phe676= (c.2028C>T) pathogenic?

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.

What condition is associated with DSTYK p.Phe676= (c.2028C>T)?

DSTYK p.Phe676= (c.2028C>T) is associated with hereditary spastic paraplegia 23, congenital anomalies of kidney and urinary tract 1 (ClinVar).

How is Autosomal recessive spastic paraplegia type 23 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

DSTYK p.Phe676=

Q: How common is DSTYK p.Phe676= (c.2028C>T) in the general population?

DSTYK p.Phe676= (c.2028C>T) is common (popmax 40.7%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2028C>T · rs1062715 · VCV260658

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 40.7%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

hereditary spastic paraplegia 23

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.65, phastCons 1
Overall
CADD	8.186	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 40.7% South Asian · 37,043/91,068 alleles

Filtering AF 40.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 40.2%

Overall 26.5% 427,240/1,613,754 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	40.7%	2
East Asian	40.5%	2
African / African-American	37.6%	3
Admixed American	33.4%	3
Amishnot grpmax-eligible	31.2%	3
Finnishnot grpmax-eligible	31.1%	3
Ashkenazi Jewishnot grpmax-eligible	28.9%	3
Remaining individualsnot grpmax-eligible	27.8%	4
Middle Eastern	24.1%	4
European (non-Finnish)	23.4%	4

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DSTYK
Protein: p.Phe676=
Coding: c.2028C>T
MANE Select: NM_015375
dbSNP: rs1062715
Type: single nucleotide variant
Location: chr1:205160191 (GRCh38)
Gene constraint: LOEUF 0.445 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.02
Residue 676: the protein kinase domain; a UniProt-annotated variant site (in cakut1; uncertain significance)

Full DSTYK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 23 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital anomalies of kidney and urinary tract 1

For Autosomal recessive spastic paraplegia type 23 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

DSTYK p.Arg626Gln Uncertain significance ★★ ⚠ same condition
DSTYK p.Gly32Asp Uncertain significance ★★ ⚠ same condition
DSTYK p.His203Gln Uncertain significance ★★ ⚠ same condition
DSTYK p.Cys641Arg Benign ★★ same condition
DSTYK p.Gln465Arg Likely pathogenic ★ same condition
DSTYK p.Gly493Ter Likely pathogenic ★ same condition
DSTYK c.1819-18T>A Uncertain significance ★ same condition
DSTYK c.1819-3C>T Conflicting classifications of pathogenicity ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dstyk-p-phe676 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown