Is AMPD2 p.Leu421= (c.1263G>A) pathogenic?

AMPD2 p.Leu421= (c.1263G>A) is classified Likely benign in AMPD2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-11). Very rare (popmax 0.000254%, nfe); Associated with AMPD2-related disorder.

What condition is associated with AMPD2 p.Leu421= (c.1263G>A)?

AMPD2 p.Leu421= (c.1263G>A) is associated with AMPD2-related disorder (ClinVar).

How common is AMPD2 p.Leu421= (c.1263G>A) in the general population?

AMPD2 p.Leu421= (c.1263G>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

AMPD2 p.Leu421=

c.1263G>A · rs139411744 · VCV3033482

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

AMPD2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.087	moderately benign-leaning
Splicing
SpliceAI	Δ0.20	donor gain, 3 bp away · raw score · deltas
Constraint at this position
Conservation	phyloP -7.4	GERP -3.6
Overall
CADD	3.471	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,686 alleles

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

Overall 0.000205% 3/1,461,276 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.Leu421=
Coding: c.1263G>A
MANE Select: NM_001368809
dbSNP: rs139411744
Type: single nucleotide variant
Location: chr1:109628265 (GRCh38)
Gene constraint: LOEUF 0.705 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.28 · 5 PDB
Residue 421: an α-helix

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

Disease context

AMPD2-related disorder

Similar variants

AMPD2 p.Glu450Ter Pathogenic ★ same condition
AMPD2 p.Glu92Ter Likely pathogenic ★ same condition
AMPD2 c.1633G>A Uncertain significance ★ same condition
AMPD2 c.2138T>C Uncertain significance ★ same condition
AMPD2 c.743T>C Uncertain significance ★ same condition
AMPD2 p.Cys288= Likely benign same condition
AMPD2 p.Glu343= Likely benign same condition
AMPD2 c.1698+1G>A Pathogenic/Likely pathogenic ★★ same type

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-leu421 (accessed [today's date]).

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