Is AMPD2 p.Ala345= (c.1035C>T) pathogenic?

AMPD2 p.Ala345= (c.1035C>T) is classified Likely benign in AMPD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-01). Ultra-rare (popmax 0.0165%, mid); Associated with pontocerebellar hypoplasia type 9.

What condition is associated with AMPD2 p.Ala345= (c.1035C>T)?

AMPD2 p.Ala345= (c.1035C>T) is associated with pontocerebellar hypoplasia type 9, hereditary spastic paraplegia 63 (ClinVar).

How common is AMPD2 p.Ala345= (c.1035C>T) in the general population?

AMPD2 p.Ala345= (c.1035C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

AMPD2 p.Ala345=

c.1035C>T · rs574448906 · VCV2055247

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

pontocerebellar hypoplasia type 9

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.083	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -4.2
Overall
CADD	1.849	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00285% 46/1,614,042 alleles · ultra-rare exomes 39/1,461,846 · genomes 7/152,196 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
South Asian	0.00879%	11,383
Admixed American	0.00667%	15,002
Remaining individualsnot grpmax-eligible	0.0048%	20,837
European (non-Finnish)	0.00246%	40,690
East Asian	0.00223%	44,886

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.Ala345=
Coding: c.1035C>T
MANE Select: NM_001368809
dbSNP: rs574448906
Type: single nucleotide variant
Location: chr1:109627858 (GRCh38)
Gene constraint: LOEUF 0.705 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.28 · 5 PDB
Residue 345: 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

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-ala345 (accessed [today's date]).

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