Is AMPD2 p.Arg508Cys (c.1522C>T) pathogenic?

AMPD2 p.Arg508Cys (c.1522C>T) is classified Uncertain significance in AMPD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-18). AlphaMissense: likely benign (0.1367); Very rare (popmax 0.00269%, afr); Associated with pontocerebellar hypoplasia type 9.

What condition is associated with AMPD2 p.Arg508Cys (c.1522C>T)?

AMPD2 p.Arg508Cys (c.1522C>T) is associated with pontocerebellar hypoplasia type 9, hereditary spastic paraplegia 63 (ClinVar).

How common is AMPD2 p.Arg508Cys (c.1522C>T) in the general population?

AMPD2 p.Arg508Cys (c.1522C>T) is very rare (popmax 0.00269%, afr) (gnomAD).

What do computational predictors say about AMPD2 p.Arg508Cys (c.1522C>T)?

AlphaMissense predicts likely benign (score 0.1367) — an in-silico prediction, not a clinical call.

AMPD2 p.Arg508Cys

c.1522C>T · rs146798795 · VCV939658

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1367 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00269%, afr)

Conditions

pontocerebellar hypoplasia type 9

Computational evidence

Protein change
AlphaMissense	0.1367	likely benign
REVEL	0.584	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP -2.3, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 3,009 bp · p 8.7e-13 · regional, not allelic
Overall
CADD	27.5	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 R562C vs ClinVar R508C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00269% African / African-American · 2/74,272 alleles

Filtering AF 0.00104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000839%

Overall 0.00145% 23/1,590,194 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00269%	37,136
European (non-Finnish)	0.00163%	61,456
Remaining individualsnot grpmax-eligible	0.00163%	61,538
South Asian	0.00113%	88,512

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.Arg508Cys
Coding: c.1522C>T
MANE Select: NM_001368809
dbSNP: rs146798795
Type: single nucleotide variant
Location: chr1:109628757 (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

Similar variants

AMPD2 p.Arg508Gly Uncertain significance ★ ⚠ same residue
AMPD2 p.Arg508= Likely benign ★ same residue
AMPD2 p.Arg508His 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

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-arg508cys (accessed [today's date]).

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