Is ADPRS p.Val46Phe (c.136G>T) pathogenic?

ADPRS p.Val46Phe (c.136G>T) is classified Uncertain significance in ADPRS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-20). AlphaMissense: likely pathogenic (0.6513); Rare (popmax 0.124%, mid); Associated with neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures.

How common is ADPRS p.Val46Phe (c.136G>T) in the general population?

ADPRS p.Val46Phe (c.136G>T) is rare (popmax 0.124%, mid) (gnomAD).

What do computational predictors say about ADPRS p.Val46Phe (c.136G>T)?

AlphaMissense predicts likely pathogenic (score 0.6513) — an in-silico prediction, not a clinical call.

ADPRS p.Val46Phe

Q: What condition is associated with ADPRS p.Val46Phe (c.136G>T)?

ADPRS p.Val46Phe (c.136G>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.136G>T · rs749889837 · VCV1029486

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6513 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.124%, 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	0.6513	likely pathogenic
REVEL	0.197	benign-leaning
SaProt	LLR -8.19	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 4,478 bp · p 0.95 · regional, not allelic
Overall
CADD	27.4	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 0.124% Middle Eastern · 7/5,646 alleles

Filtering AF 0.0581% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0412%

Overall 0.00319% 47/1,474,224 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.124%	807
South Asian	0.0153%	6,515
Remaining individualsnot grpmax-eligible	0.00884%	11,315
Admixed American	0.00522%	19,147
European (non-Finnish)	0.00197%	50,772

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.Val46Phe
Coding: c.136G>T
MANE Select: NM_017825
dbSNP: rs749889837
Type: single nucleotide variant
Location: chr1:36089040 (GRCh38)
Gene constraint: LOEUF 1.155 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.70 · 14 PDB

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.Val46Leu Uncertain significance ★ ⚠ same residue
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.Arg175Trp Uncertain significance ★★ ⚠ same condition
ADPRS p.Tyr164Cys Uncertain significance ★★ ⚠ same condition
ADPRS p.Gln194Ter 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-val46phe (accessed [today's date]).

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