Is AMPD2 p.Arg620His (c.1859G>A) pathogenic?

AMPD2 p.Arg620His (c.1859G>A) is classified Pathogenic/Likely pathogenic in AMPD2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-06-12). AlphaMissense: likely pathogenic (0.9568); Very rare (popmax 0.00119%, nfe); Associated with pontocerebellar hypoplasia type 9.

What condition is associated with AMPD2 p.Arg620His (c.1859G>A)?

AMPD2 p.Arg620His (c.1859G>A) is associated with pontocerebellar hypoplasia type 9, hereditary spastic paraplegia 63, pontocerebellar hypoplasia (ClinVar).

How common is AMPD2 p.Arg620His (c.1859G>A) in the general population?

AMPD2 p.Arg620His (c.1859G>A) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about AMPD2 p.Arg620His (c.1859G>A)?

AlphaMissense predicts likely pathogenic (score 0.9568) — an in-silico prediction, not a clinical call.

AMPD2 p.Arg620His

c.1859G>A · rs587777395 · VCV132813

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9568 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

pontocerebellar hypoplasia type 9

Computational evidence

Protein change
AlphaMissense	0.9568	likely pathogenic ✓ concordant with ClinVar
REVEL	0.913	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	34.0	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 R674H vs ClinVar R620H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00119% European (non-Finnish) · 14/1,179,792 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00093% 15/1,613,200 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00157%	63,632
European (non-Finnish)grpmax	0.00119%	84,271

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg620His
Coding: c.1859G>A
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

Also linked: hereditary spastic paraplegia 63 pontocerebellar hypoplasia

Similar variants

AMPD2 p.Arg620Leu 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-arg620his (accessed [today's date]).

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