Is DSTYK p.Cys641Arg (c.1921T>C) pathogenic?

DSTYK p.Cys641Arg (c.1921T>C) is classified Benign in DSTYK (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0454); Common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele; Associated with hereditary spastic paraplegia 23.

What condition is associated with DSTYK p.Cys641Arg (c.1921T>C)?

DSTYK p.Cys641Arg (c.1921T>C) 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.

What do computational predictors say about DSTYK p.Cys641Arg (c.1921T>C)?

AlphaMissense predicts likely benign (score 0.0454) — an in-silico prediction, not a clinical call.

DSTYK p.Cys641Arg

Q: How common is DSTYK p.Cys641Arg (c.1921T>C) in the general population?

DSTYK p.Cys641Arg (c.1921T>C) is common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1921T>C · rs3851294 · VCV260657

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0454 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 23

Computational evidence

Protein change
AlphaMissense	0.0454	likely benign
REVEL	0.207	benign-leaning
SaProt	LLR -6.41	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 5.9	GERP 1.1, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 54 kb · p 2.6e-11 · regional, not allelic
Overall
CADD	18.74	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 100% East Asian · 44,868/44,880 alleles

Filtering AF 99.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 98.9%

Overall 91.8% 1,480,953/1,614,030 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	100%	1
African / African-American	98.6%	1
Admixed American	95.7%	1
South Asian	94.3%	1
Amishnot grpmax-eligible	92.9%	1
Remaining individualsnot grpmax-eligible	92.4%	1
Finnishnot grpmax-eligible	92.2%	1
European (non-Finnish)	90.6%	1
Ashkenazi Jewishnot grpmax-eligible	90.6%	1
Middle Eastern	90.3%	1

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.Cys641Arg
Coding: c.1921T>C
MANE Select: NM_015375
dbSNP: rs3851294
Type: single nucleotide variant
Location: chr1:205161285 (GRCh38)
Gene constraint: LOEUF 0.445 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.02
Residue 641: 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.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
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-cys641arg (accessed [today's date]).

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