Is ADPRS p.Met332fs (c.993del) pathogenic?

ADPRS p.Met332fs (c.993del) is classified Uncertain significance in ADPRS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-30). Ultra-rare (popmax 0.0107%, afr); Associated with neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures.

How common is ADPRS p.Met332fs (c.993del) in the general population?

ADPRS p.Met332fs (c.993del) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

ADPRS p.Met332fs

Q: What condition is associated with ADPRS p.Met332fs (c.993del)?

ADPRS p.Met332fs (c.993del) 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.993del · VCV4854030

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Conditions

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (6 of 6) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.23	GERP -0.32, phastCons 0.57
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0107% African / African-American · 8/74,924 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00526% 8/152,216 alleles · ultra-rare

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.Met332fs
Coding: c.993del
MANE Select: NM_017825
Type: Deletion
Location: chr1:36093285 (GRCh38)
Gene constraint: LOEUF 1.155 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.70 · 14 PDB
Residue 332: 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.Ala139fs Pathogenic ★★ same condition
ADPRS p.Thr49fs Pathogenic ★ same condition
ADPRS p.Val98fs Likely pathogenic ★ same condition
ADPRS p.Lys248_Ile249delinsAsn Conflicting classifications of pathogenicity ★ same condition
ADPRS p.Lys213fs Uncertain significance same condition
ADPRS p.Gln106Ter Pathogenic/Likely pathogenic ★★ same condition
ADPRS p.Ser177Leu Likely pathogenic ★★ same condition
ADPRS p.Thr79Pro Pathogenic/Likely 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-met332fs (accessed [today's date]).

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