Is AMPD2 p.Glu286Lys (c.856G>A) pathogenic?

AMPD2 p.Glu286Lys (c.856G>A) is classified Uncertain significance in AMPD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-23). AlphaMissense: likely benign (0.0904); Very rare (popmax 0.00448%, eas); Associated with pontocerebellar hypoplasia type 9.

What condition is associated with AMPD2 p.Glu286Lys (c.856G>A)?

AMPD2 p.Glu286Lys (c.856G>A) is associated with pontocerebellar hypoplasia type 9, hereditary spastic paraplegia 63 (ClinVar).

How common is AMPD2 p.Glu286Lys (c.856G>A) in the general population?

AMPD2 p.Glu286Lys (c.856G>A) is very rare (popmax 0.00448%, eas) (gnomAD).

What do computational predictors say about AMPD2 p.Glu286Lys (c.856G>A)?

AlphaMissense predicts likely benign (score 0.0904) — an in-silico prediction, not a clinical call.

AMPD2 p.Glu286Lys

c.856G>A · rs1255257133 · VCV1477455

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0904 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00448%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pontocerebellar hypoplasia type 9

Computational evidence

Protein change
AlphaMissense	0.0904	likely benign
REVEL	0.28	benign-leaning
SaProt	LLR -15.37	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,721 bp · p 0.065 · regional, not allelic
Overall
CADD	24.5	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 E340K vs ClinVar E286K) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00448% East Asian · 2/44,686 alleles

Filtering AF 0.000742% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000278%

Overall 0.000125% 2/1,604,686 alleles · very rare

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.Glu286Lys
Coding: c.856G>A
MANE Select: NM_001368809
dbSNP: rs1255257133
Type: single nucleotide variant
Location: chr1:109627312 (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-p-glu286lys (accessed [today's date]).

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