Is AMPD2 p.Arg486Gln (c.1457G>A) pathogenic?

AMPD2 p.Arg486Gln (c.1457G>A) is classified Conflicting classifications of pathogenicity in AMPD2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-03-14). AlphaMissense: likely pathogenic (0.9872); Very rare (popmax 0.0011%, sas); Associated with hereditary spastic paraplegia 63.

What condition is associated with AMPD2 p.Arg486Gln (c.1457G>A)?

AMPD2 p.Arg486Gln (c.1457G>A) is associated with hereditary spastic paraplegia 63, pontocerebellar hypoplasia type 9 (ClinVar).

How common is AMPD2 p.Arg486Gln (c.1457G>A) in the general population?

AMPD2 p.Arg486Gln (c.1457G>A) is very rare (popmax 0.0011%, sas) (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.Arg486Gln (c.1457G>A)?

AlphaMissense predicts likely pathogenic (score 0.9872) — an in-silico prediction, not a clinical call.

AMPD2 p.Arg486Gln

c.1457G>A · rs192669225 · VCV183289

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9872 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

hereditary spastic paraplegia 63

Computational evidence

Protein change
AlphaMissense	0.9872	likely pathogenic
REVEL	0.962	strongly pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	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

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R540Q vs ClinVar R486Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,040 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000547% 8/1,461,536 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	63,904
South Asiangrpmax	0.0011%	91,040
European (non-Finnish)	0.000509%	196,655

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg486Gln
Coding: c.1457G>A
MANE Select: NM_001368809
dbSNP: rs192669225
Type: single nucleotide variant
Location: chr1:109628692 (GRCh38)
Gene constraint: LOEUF 0.705 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.28 · 5 PDB
Residue 486: a β-strand

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-arg486gln (accessed [today's date]).

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