Is DSTYK p.Arg660Gln (c.1979G>A) pathogenic?

DSTYK p.Arg660Gln (c.1979G>A) is classified Uncertain significance in DSTYK (ClinVar, Single submitter, 2 submitters; last evaluated 2022-01-16). AlphaMissense: ambiguous (0.5246); Very rare (popmax 0.0011%, sas); Associated with hereditary spastic paraplegia 23.

What condition is associated with DSTYK p.Arg660Gln (c.1979G>A)?

DSTYK p.Arg660Gln (c.1979G>A) is associated with hereditary spastic paraplegia 23, congenital anomalies of kidney and urinary tract 1 (ClinVar).

How common is DSTYK p.Arg660Gln (c.1979G>A) in the general population?

DSTYK p.Arg660Gln (c.1979G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Autosomal recessive spastic paraplegia type 23 inherited?

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

What do computational predictors say about DSTYK p.Arg660Gln (c.1979G>A)?

AlphaMissense predicts ambiguous (score 0.5246) — an in-silico prediction, not a clinical call.

DSTYK p.Arg660Gln

c.1979G>A · rs1035239987 · VCV1952039

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5246 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

hereditary spastic paraplegia 23

Computational evidence

Protein change
AlphaMissense	0.5246	ambiguous
REVEL	0.48	indeterminate
SaProt	LLR -13.47	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 54 kb · p 2.6e-11 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,080 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000616% 9/1,461,826 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,253
South Asiangrpmax	0.0011%	91,080
European (non-Finnish)	0.000508%	196,668

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg660Gln
Coding: c.1979G>A
MANE Select: NM_015375
dbSNP: rs1035239987
Type: single nucleotide variant
Location: chr1:205160240 (GRCh38)
Gene constraint: LOEUF 0.445 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.02
Residue 660: the protein kinase domain; a UniProt-annotated variant site (in cakut1; uncertain significance); a binding site

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-p-arg660gln (accessed [today's date]).

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