Is AMPD2 p.Pro90fs (c.269del) pathogenic?

AMPD2 p.Pro90fs (c.269del) is classified Likely pathogenic in AMPD2 (ClinVar, Single submitter, 1 submitter). Very rare (popmax 0.00223%, eas); Associated with hereditary spastic paraplegia 63.

What condition is associated with AMPD2 p.Pro90fs (c.269del)?

AMPD2 p.Pro90fs (c.269del) is associated with hereditary spastic paraplegia 63, pontocerebellar hypoplasia type 9 (ClinVar).

How common is AMPD2 p.Pro90fs (c.269del) in the general population?

AMPD2 p.Pro90fs (c.269del) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Autosomal recessive spastic paraplegia type 63 inherited?

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

AMPD2 p.Pro90fs

c.269del · VCV3382962

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

hereditary spastic paraplegia 63

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.8	GERP 1.6, phastCons 1
Overall
CADD	33.0	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 0.00223% East Asian · 1/44,876 alleles

Overall 0.000657% 1/152,318 alleles · very 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: AMPD2
Protein: p.Pro90fs
Coding: c.269del
MANE Select: NM_001368809
Type: Deletion
Location: chr1:109625705 (GRCh38)
Gene constraint: LOEUF 0.705 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.28 · 5 PDB

Full AMPD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 63 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pontocerebellar hypoplasia type 9

For Autosomal recessive spastic paraplegia type 63 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

AMPD2 p.Pro90= Likely benign ★ same residue
AMPD2 p.Gly35fs Pathogenic/Likely pathogenic ★★ same condition
AMPD2 p.Leu216fs Pathogenic/Likely pathogenic ★★ same condition
AMPD2 c.1408-3_1418del Likely pathogenic ★ same condition
AMPD2 p.Ala89fs Pathogenic ★ same condition
AMPD2 p.Gln101fs Likely pathogenic ★ same condition
AMPD2 p.Lys14fs Pathogenic ★ same condition
AMPD2 p.Pro442fs 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/ampd2-p-pro90fs (accessed [today's date]).

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