Is AMPD2 p.Arg324Trp (c.970C>T) pathogenic?

AMPD2 p.Arg324Trp (c.970C>T) is classified Conflicting classifications of pathogenicity in AMPD2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-08-08). AlphaMissense: likely pathogenic (0.9853); Very rare (popmax 0.0022%, sas); Associated with hereditary spastic paraplegia 63.

What condition is associated with AMPD2 p.Arg324Trp (c.970C>T)?

AMPD2 p.Arg324Trp (c.970C>T) is associated with hereditary spastic paraplegia 63, pontocerebellar hypoplasia type 9 (ClinVar).

How common is AMPD2 p.Arg324Trp (c.970C>T) in the general population?

AMPD2 p.Arg324Trp (c.970C>T) is very rare (popmax 0.0022%, 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.Arg324Trp (c.970C>T)?

AlphaMissense predicts likely pathogenic (score 0.9853) — an in-silico prediction, not a clinical call.

AMPD2 p.Arg324Trp

c.970C>T · rs776868175 · VCV1332816

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9853 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary spastic paraplegia 63

Computational evidence

Protein change
AlphaMissense	0.9853	likely pathogenic
REVEL	0.942	strongly pathogenic-leaning
SaProt	LLR -16.36	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.94 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 625 bp · p 2.1e-07 · 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 R378W vs ClinVar R324W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,070 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000958% 14/1,461,818 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,535
Admixed American	0.00167%	60,012
European (non-Finnish)	0.000932%	107,272

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.Arg324Trp
Coding: c.970C>T
MANE Select: NM_001368809
dbSNP: rs776868175
Type: single nucleotide variant
Location: chr1:109627793 (GRCh38)
Gene constraint: LOEUF 0.705 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.28 · 5 PDB
Residue 324: an α-helix

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.Arg324Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
AMPD2 p.Arg324Pro 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.Arg620His Pathogenic/Likely pathogenic ★★ same condition
AMPD2 p.Arg789His Likely pathogenic ★★ same condition
AMPD2 p.Glu174Ter Pathogenic/Likely pathogenic ★★ 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-arg324trp (accessed [today's date]).

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