Is AMPD2 p.Arg163Pro (c.488G>C) pathogenic?

AMPD2 p.Arg163Pro (c.488G>C) is classified Uncertain significance in AMPD2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-10-12). AlphaMissense: likely benign (0.194); Very rare (popmax 0.00674%, amr); Associated with pontocerebellar hypoplasia type 9.

What condition is associated with AMPD2 p.Arg163Pro (c.488G>C)?

AMPD2 p.Arg163Pro (c.488G>C) is associated with pontocerebellar hypoplasia type 9, hereditary spastic paraplegia 63, hereditary spastic paraplegia (ClinVar).

How common is AMPD2 p.Arg163Pro (c.488G>C) in the general population?

AMPD2 p.Arg163Pro (c.488G>C) is very rare (popmax 0.00674%, amr) (gnomAD).

What do computational predictors say about AMPD2 p.Arg163Pro (c.488G>C)?

AlphaMissense predicts likely benign (score 0.194) — an in-silico prediction, not a clinical call.

AMPD2 p.Arg163Pro

c.488G>C · rs138175138 · VCV424663

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.194 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00674%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

pontocerebellar hypoplasia type 9

Computational evidence

Protein change
AlphaMissense	0.194	likely benign
REVEL	0.249	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,721 bp · p 0.065 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 R217P vs ClinVar R163P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00674% Admixed American · 4/59,304 alleles

Filtering AF 0.00227% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00143% 23/1,611,950 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00674%	14,826
Remaining individualsnot grpmax-eligible	0.0016%	62,348
European (non-Finnish)	0.00153%	65,517

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.Arg163Pro
Coding: c.488G>C
MANE Select: NM_001368809
dbSNP: rs138175138
Type: single nucleotide variant
Location: chr1:109626384 (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

pontocerebellar hypoplasia type 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia 63 hereditary spastic paraplegia

Similar variants

AMPD2 p.Arg163Trp Uncertain significance ★ ⚠ same residue
AMPD2 p.Arg163Gln Uncertain significance ★★ ⚠ same residue
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

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-arg163pro (accessed [today's date]).

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