Is AMPD2 p.Arg620Leu (c.1859G>T) pathogenic?

AMPD2 p.Arg620Leu (c.1859G>T) is classified Likely pathogenic in AMPD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-13). AlphaMissense: likely pathogenic (0.9529); Very rare (popmax 0.000254%, nfe); Associated with pontocerebellar hypoplasia type 9.

What condition is associated with AMPD2 p.Arg620Leu (c.1859G>T)?

AMPD2 p.Arg620Leu (c.1859G>T) is associated with pontocerebellar hypoplasia type 9 (ClinVar).

How common is AMPD2 p.Arg620Leu (c.1859G>T) in the general population?

AMPD2 p.Arg620Leu (c.1859G>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about AMPD2 p.Arg620Leu (c.1859G>T)?

AlphaMissense predicts likely pathogenic (score 0.9529) — an in-silico prediction, not a clinical call.

AMPD2 p.Arg620Leu

c.1859G>T · rs587777395 · VCV1098294

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9529 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

pontocerebellar hypoplasia type 9

Computational evidence

Protein change
AlphaMissense	0.9529	likely pathogenic ✓ concordant with ClinVar
REVEL	0.906	moderately 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 R674L vs ClinVar R620L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,784 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,126 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.Arg620Leu
Coding: c.1859G>T
MANE Select: NM_001368809
dbSNP: rs587777395
Type: single nucleotide variant
Location: chr1:109629487 (GRCh38)
Gene constraint: LOEUF 0.705 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.28 · 5 PDB
Residue 620: a UniProt-annotated variant site (in pch9); an α-helix

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

Similar variants

AMPD2 p.Arg620His Pathogenic/Likely pathogenic ★★ same residue
AMPD2 p.Arg620Ser Likely pathogenic ★ 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.Arg789His Likely pathogenic ★★ same condition
AMPD2 p.Glu174Ter Pathogenic/Likely pathogenic ★★ same condition
AMPD2 c.1080+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-arg620leu (accessed [today's date]).

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