Is DSTYK p.His203Gln (c.609T>G) pathogenic?

DSTYK p.His203Gln (c.609T>G) is classified Uncertain significance in DSTYK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-11-22). AlphaMissense: likely benign (0.1774); Rare (popmax 0.148%, mid); Associated with hereditary spastic paraplegia 23.

What condition is associated with DSTYK p.His203Gln (c.609T>G)?

DSTYK p.His203Gln (c.609T>G) is associated with hereditary spastic paraplegia 23 (ClinVar).

How common is DSTYK p.His203Gln (c.609T>G) in the general population?

DSTYK p.His203Gln (c.609T>G) is rare (popmax 0.148%, mid) (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.His203Gln (c.609T>G)?

AlphaMissense predicts likely benign (score 0.1774) — an in-silico prediction, not a clinical call.

DSTYK p.His203Gln

c.609T>G · rs748982270 · VCV807907

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1774 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.148%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 23

Computational evidence

Protein change
AlphaMissense	0.1774	likely benign
REVEL	0.21	benign-leaning
SaProt	LLR -5.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.48	GERP -3.2, phastCons 0.78
Regional constraint	o/e 0.77	unconstrained · MANE · 54 kb · p 2.6e-11 · regional, not allelic
Overall
CADD	14.02	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.148% Middle Eastern · 9/6,084 alleles

Filtering AF 0.0772% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0576%

Overall 0.000867% 14/1,614,024 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.148%	676
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00133%	74,926
European (non-Finnish)	0.000254%	393,331

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.His203Gln
Coding: c.609T>G
MANE Select: NM_015375
dbSNP: rs748982270
Type: single nucleotide variant
Location: chr1:205187463 (GRCh38)
Gene constraint: LOEUF 0.445 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.02
Residue 203: 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

For Autosomal recessive spastic paraplegia type 23 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

DSTYK p.Gly32Asp Uncertain significance ★★ ⚠ same condition
DSTYK p.Cys641Arg Benign ★★ same condition
DSTYK p.Phe676= Benign ★★ same condition
DSTYK c.654+1G>A Conflicting classifications of pathogenicity ★ ⚠ same condition
DSTYK p.Arg390His Uncertain significance ★ ⚠ same condition
DSTYK p.Arg462Ter Conflicting classifications of pathogenicity ★ ⚠ same condition
DSTYK p.Arg660Gln Uncertain significance ★ same condition
DSTYK p.Glu439Asp 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-his203gln (accessed [today's date]).

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