Is PDYN p.Arg138Ser (c.414G>T) pathogenic?

PDYN p.Arg138Ser (c.414G>T) is classified Conflicting classifications of pathogenicity in PDYN (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-12-27). AlphaMissense: likely benign (0.1026); Ultra-rare (popmax 0.01%, amr); Associated with spinocerebellar ataxia type 23.

What condition is associated with PDYN p.Arg138Ser (c.414G>T)?

PDYN p.Arg138Ser (c.414G>T) is associated with spinocerebellar ataxia type 23 (ClinVar).

How common is PDYN p.Arg138Ser (c.414G>T) in the general population?

PDYN p.Arg138Ser (c.414G>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

How is Spinocerebellar ataxia type 23 inherited?

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

What do computational predictors say about PDYN p.Arg138Ser (c.414G>T)?

AlphaMissense predicts likely benign (score 0.1026) — an in-silico prediction, not a clinical call.

PDYN p.Arg138Ser

c.414G>T · rs267606941 · VCV18458

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1026 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

spinocerebellar ataxia type 23

Computational evidence

Protein change
AlphaMissense	0.1026	likely benign
REVEL	0.46	indeterminate
SaProt	LLR -4.87	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.8	GERP 0.3, phastCons 0.022
Regional constraint	o/e 1.06	unconstrained · MANE · 2,758 bp · p 0.27 · regional, not allelic
Overall
CADD	16.47	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 0.01% Admixed American · 6/59,996 alleles

Filtering AF 0.00527% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.0052% 84/1,614,078 alleles · ultra-rare exomes 72/1,461,884 · genomes 12/152,194 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,999
European (non-Finnish)	0.00644%	15,527
Remaining individualsnot grpmax-eligible	0.0032%	31,243

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: PDYN
Protein: p.Arg138Ser
Coding: c.414G>T
MANE Select: NM_024411
dbSNP: rs267606941
Type: single nucleotide variant
Location: chr20:1980674 (GRCh38)
Gene constraint: LOEUF 0.769 · pLI 0.49 (gnomAD)
Structure: AlphaFold pLDDT 58.95 · 8 PDB
Residue 138: a UniProt-annotated variant site (in sca23; pdyn, dynorphin a and dynorphin b are located in purkinje cells as observed in control cerebellum, but cerebellar tissue with the mutation has decreased levels of slc1a6 and calb1, both of which are markers of purkinje cells; slc1a6 accumulates and aggregates in patient cerebellar tissue)

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

Disease context

spinocerebellar ataxia type 23 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Spinocerebellar ataxia type 23 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

PDYN p.Arg180Cys Uncertain significance ★★ ⚠ same condition
PDYN p.Arg231Trp Uncertain significance ★★ ⚠ same condition
PDYN p.Glu242Lys Uncertain significance ★★ ⚠ same condition
PDYN p.Gly191Trp Uncertain significance ★★ ⚠ same condition
PDYN c.*1030C>T Benign ★★ same condition
PDYN c.*356T>C Benign ★★ same condition
PDYN c.*743T>C Benign ★★ same condition
PDYN p.Glu192Val Benign/Likely benign ★★ 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/pdyn-p-arg138ser (accessed [today's date]).

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