Is ADPRS p.Arg175Trp (c.523C>T) pathogenic?

ADPRS p.Arg175Trp (c.523C>T) is classified Uncertain significance in ADPRS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-05). AlphaMissense: likely benign (0.198); Ultra-rare (popmax 0.0166%, mid); Associated with neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures.

How common is ADPRS p.Arg175Trp (c.523C>T) in the general population?

ADPRS p.Arg175Trp (c.523C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about ADPRS p.Arg175Trp (c.523C>T)?

AlphaMissense predicts likely benign (score 0.198) — an in-silico prediction, not a clinical call.

ADPRS p.Arg175Trp

Q: What condition is associated with ADPRS p.Arg175Trp (c.523C>T)?

ADPRS p.Arg175Trp (c.523C>T) is associated with neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures (ClinVar).

Q: How is Childhood-onset stress-induced neurodegenerative ataxia-seizure syndrome inherited?

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

c.523C>T · rs759989977 · VCV3090436

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.198 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures

Computational evidence

Protein change
AlphaMissense	0.198	likely benign
REVEL	0.271	benign-leaning
SaProt	LLR -14.87	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.8	GERP 1.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 4,478 bp · p 0.95 · regional, not allelic
Overall
CADD	29.0	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 0.0166% Middle Eastern · 1/6,026 alleles

Filtering AF 0.00144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00144% 23/1,601,200 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,026
South Asian	0.00445%	22,481
Remaining individualsnot grpmax-eligible	0.00323%	30,949
African / African-American	0.00268%	37,355
Finnishnot grpmax-eligible	0.00157%	63,730
European (non-Finnish)	0.00111%	90,086

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: ADPRS
Protein: p.Arg175Trp
Coding: c.523C>T
MANE Select: NM_017825
dbSNP: rs759989977
Type: single nucleotide variant
Location: chr1:36091916 (GRCh38)
Gene constraint: LOEUF 1.155 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.70 · 14 PDB
Residue 175: a UniProt-annotated variant site (in condsias; no detectable protein in patient fibroblasts); an α-helix

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

Disease context

neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Childhood-onset stress-induced neurodegenerative ataxia-seizure syndrome (Orphanet):

Inheritance: Autosomal recessive

Similar variants

ADPRS p.Gln106Ter Pathogenic/Likely pathogenic ★★ same condition
ADPRS p.Ser177Leu Likely pathogenic ★★ same condition
ADPRS p.Thr79Pro Pathogenic/Likely pathogenic ★★ same condition
ADPRS p.Val335Gly Pathogenic/Likely pathogenic ★★ same condition
ADPRS p.Tyr164Cys Uncertain significance ★★ ⚠ same condition
ADPRS p.Val46Phe Uncertain significance ★★ ⚠ same condition
ADPRS p.Gln194Ter Pathogenic ★ same condition
ADPRS p.Gln214Ter Pathogenic ★ 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/adprs-p-arg175trp (accessed [today's date]).

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