Is AMPD2 p.Arg270His (c.809G>A) pathogenic?

AMPD2 p.Arg270His (c.809G>A) is classified Uncertain significance in AMPD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-03). AlphaMissense: likely benign (0.0885); Very rare (popmax 0.00442%, sas); Associated with hereditary spastic paraplegia 63.

What condition is associated with AMPD2 p.Arg270His (c.809G>A)?

AMPD2 p.Arg270His (c.809G>A) is associated with hereditary spastic paraplegia 63, pontocerebellar hypoplasia type 9 (ClinVar).

How common is AMPD2 p.Arg270His (c.809G>A) in the general population?

AMPD2 p.Arg270His (c.809G>A) is very rare (popmax 0.00442%, sas) (gnomAD).

How is Autosomal recessive spastic paraplegia type 63 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about AMPD2 p.Arg270His (c.809G>A)?

AlphaMissense predicts likely benign (score 0.0885) — an in-silico prediction, not a clinical call.

AMPD2 p.Arg270His

c.809G>A · rs749468757 · VCV1510265

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0885 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00442%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary spastic paraplegia 63

Computational evidence

Protein change
AlphaMissense	0.0885	likely benign
REVEL	0.344	indeterminate
SaProt	LLR -13.14	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 0.76, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,721 bp · p 0.065 · regional, not allelic
Overall
CADD	25.6	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 R324H vs ClinVar R270H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00442% South Asian · 4/90,504 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000895%

Overall 0.00186% 30/1,609,960 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00482%	20,755
South Asiangrpmax	0.00442%	22,626
African / African-American	0.00401%	24,958
Admixed American	0.00168%	59,648
European (non-Finnish)	0.00161%	61,992

Remaining individuals 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.Arg270His
Coding: c.809G>A
MANE Select: NM_001368809
dbSNP: rs749468757
Type: single nucleotide variant
Location: chr1:109627265 (GRCh38)
Gene constraint: LOEUF 0.705 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.28 · 5 PDB
Residue 270: a β-strand

Full AMPD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 63 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pontocerebellar hypoplasia type 9

For Autosomal recessive spastic paraplegia type 63 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

AMPD2 p.Arg270Cys 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
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-arg270his (accessed [today's date]).

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