Is DSTYK c.654+1G>A pathogenic?

DSTYK c.654+1G>A is classified Conflicting classifications of pathogenicity in DSTYK (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-03-25). Ultra-rare (popmax 0.0845%, amr); Associated with hereditary spastic paraplegia 23.

What condition is associated with DSTYK c.654+1G>A?

DSTYK c.654+1G>A is associated with hereditary spastic paraplegia 23, congenital anomalies of kidney and urinary tract 1 (ClinVar).

How common is DSTYK c.654+1G>A in the general population?

DSTYK c.654+1G>A is ultra-rare (popmax 0.0845%, amr) (gnomAD).

How is Autosomal recessive spastic paraplegia type 23 inherited?

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

DSTYK c.654+1G>A

rs201091809 · VCV60684

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0845%, amr)

Conditions

hereditary spastic paraplegia 23

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function in a LoF-intolerant gene
Splicing
Splice region	donor +1	canonical splice dinucleotide (donor +1) · inside the BP7-excluded zone
SpliceAI	Δ0.96	donor loss, 1 bp away · masked 0 · deltas
Pangolin	Δ0.69	loss · gain 0.29 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Non-coding constraint	Z 3.33	1 kb window · o/e 0.77 · regional · uncalibrated
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0845% Admixed American · 50/59,186 alleles

Filtering AF 0.0657% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0591%

Overall 0.0367% 588/1,602,522 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0845%	1,184
European (non-Finnish)	0.0437%	2,286
Remaining individualsnot grpmax-eligible	0.029%	3,443
Middle Eastern	0.0166%	6,012
African / African-American	0.00668%	14,960
Finnishnot grpmax-eligible	0.00157%	63,660

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
Coding: c.654+1G>A
MANE Select: NM_015375
dbSNP: rs201091809
Type: single nucleotide variant
Location: chr1:205187417 (GRCh38)
Gene constraint: LOEUF 0.445 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.02

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.Phe676= 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

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-c-654-plus-1g-a (accessed [today's date]).

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