Is AMPD2 c.-149G>A pathogenic?

AMPD2 c.-149G>A is classified Uncertain significance in AMPD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-17). AlphaMissense: likely benign (0.1503); Very rare (popmax 0.00853%, amr); Associated with pontocerebellar hypoplasia type 9.

What condition is associated with AMPD2 c.-149G>A?

AMPD2 c.-149G>A is associated with pontocerebellar hypoplasia type 9, hereditary spastic paraplegia 63 (ClinVar).

How common is AMPD2 c.-149G>A in the general population?

AMPD2 c.-149G>A is very rare (popmax 0.00853%, amr) (gnomAD).

What do computational predictors say about AMPD2 c.-149G>A?

AlphaMissense predicts likely benign (score 0.1503) — an in-silico prediction, not a clinical call.

AMPD2 c.-149G>A

rs773946980 · VCV1524824

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1503 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00853%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

pontocerebellar hypoplasia type 9

Computational evidence

Protein change
AlphaMissense	0.1503	likely benign
REVEL	0.16	moderately 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 12	GERP 1.6, phastCons 1
Overall
CADD	21.7	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00853% Admixed American · 5/58,626 alleles

Filtering AF 0.00329% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00211%

Overall 0.000485% 7/1,443,686 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00853%	11,725
Remaining individualsnot grpmax-eligible	0.00162%	61,638
European (non-Finnish)	8.54e-05%	1,171,446

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
Coding: c.-149G>A
MANE Select: NM_001368809
dbSNP: rs773946980
Type: single nucleotide variant
Location: chr1:109621027 (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 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-c-minus-149g-a (accessed [today's date]).

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