Is AMPD2 p.Pro721Leu (c.2162C>T) pathogenic?

AMPD2 p.Pro721Leu (c.2162C>T) is classified Uncertain significance in AMPD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-06). AlphaMissense: likely pathogenic (0.9809); Absent from gnomAD v4.1; Associated with hereditary spastic paraplegia 63.

What condition is associated with AMPD2 p.Pro721Leu (c.2162C>T)?

AMPD2 p.Pro721Leu (c.2162C>T) is associated with hereditary spastic paraplegia 63, pontocerebellar hypoplasia type 9 (ClinVar).

How common is AMPD2 p.Pro721Leu (c.2162C>T) in the general population?

AMPD2 p.Pro721Leu (c.2162C>T) is absent from gnomAD v4.1 (gnomAD).

How is Autosomal recessive spastic paraplegia type 63 inherited?

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

What do computational predictors say about AMPD2 p.Pro721Leu (c.2162C>T)?

AlphaMissense predicts likely pathogenic (score 0.9809) — an in-silico prediction, not a clinical call.

AMPD2 p.Pro721Leu

c.2162C>T · rs1651160667 · VCV1444085

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9809 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

hereditary spastic paraplegia 63

Computational evidence

Protein change
AlphaMissense	0.9809	likely pathogenic
REVEL	0.906	moderately pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.78 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 3,009 bp · p 8.7e-13 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P775L vs ClinVar P721L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AMPD2
Protein: p.Pro721Leu
Coding: c.2162C>T
MANE Select: NM_001368809
dbSNP: rs1651160667
Type: single nucleotide variant
Location: chr1:109630687 (GRCh38)
Gene constraint: LOEUF 0.705 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.28 · 5 PDB
Residue 721: an α-helix

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 c.1698+1G>A Pathogenic/Likely pathogenic ★★ same condition
AMPD2 p.Arg353Ter Pathogenic/Likely pathogenic ★★ same condition
AMPD2 p.Arg449Ter Pathogenic/Likely pathogenic ★★ same condition
AMPD2 p.Arg620His Pathogenic/Likely pathogenic ★★ same condition
AMPD2 p.Arg789His Likely pathogenic ★★ same condition
AMPD2 p.Glu174Ter Pathogenic/Likely pathogenic ★★ same condition
AMPD2 c.1080+3G>A Uncertain significance ★★ same condition
AMPD2 c.353+3G>A Uncertain significance ★★ 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-pro721leu (accessed [today's date]).

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