Is AMPD1 p.Arg724Leu (c.2171G>T) pathogenic?

AMPD1 p.Arg724Leu (c.2171G>T) is classified Uncertain significance in AMPD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-11). AlphaMissense: likely pathogenic (0.985); Very rare (popmax 0.00133%, afr); Associated with myopathy due to myoadenylate deaminase deficiency.

What condition is associated with AMPD1 p.Arg724Leu (c.2171G>T)?

AMPD1 p.Arg724Leu (c.2171G>T) is associated with myopathy due to myoadenylate deaminase deficiency (ClinVar).

How common is AMPD1 p.Arg724Leu (c.2171G>T) in the general population?

AMPD1 p.Arg724Leu (c.2171G>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about AMPD1 p.Arg724Leu (c.2171G>T)?

AlphaMissense predicts likely pathogenic (score 0.985) — an in-silico prediction, not a clinical call.

AMPD1 p.Arg724Leu

c.2171G>T · rs146036570 · VCV1478480

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.985 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

myopathy due to myoadenylate deaminase deficiency

Computational evidence

Protein change
AlphaMissense	0.985	likely pathogenic · top 7% in AMPD1
REVEL	0.931	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 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 862 bp · p 0.00064 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R757L vs ClinVar R724L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,000 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000372% 6/1,614,016 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,000
South Asian	0.0011%	91,070
European (non-Finnish)	0.000339%	294,992

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: AMPD1
Protein: p.Arg724Leu
Coding: c.2171G>T
MANE Select: NM_000036
dbSNP: rs146036570
Type: single nucleotide variant
Location: chr1:114673187 (GRCh38)
Gene constraint: LOEUF 1.036 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.84

Full AMPD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

myopathy due to myoadenylate deaminase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AMPD1 p.Arg724His Uncertain significance ★★ ⚠ same residue
AMPD1 p.Arg724Cys Uncertain significance ★ ⚠ same residue
AMPD1 p.Arg724Pro Uncertain significance ★ ⚠ same residue
AMPD1 p.Gln653Ter Pathogenic/Likely pathogenic ★★ same condition
AMPD1 c.1388+5G>A Uncertain significance ★★ same condition
AMPD1 c.1974+1G>A Uncertain significance ★★ same condition
AMPD1 c.-42C>T Uncertain significance ★★ ⚠ same condition
AMPD1 p.Ala308Thr 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/ampd1-p-arg724leu (accessed [today's date]).

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