Is AMPD1 p.Arg75Cys (c.223C>T) pathogenic?

AMPD1 p.Arg75Cys (c.223C>T) is classified Uncertain significance in AMPD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-23). AlphaMissense: likely benign (0.1472); Ultra-rare (popmax 0.03%, amr); Associated with myopathy due to myoadenylate deaminase deficiency.

What condition is associated with AMPD1 p.Arg75Cys (c.223C>T)?

AMPD1 p.Arg75Cys (c.223C>T) is associated with myopathy due to myoadenylate deaminase deficiency (ClinVar).

How common is AMPD1 p.Arg75Cys (c.223C>T) in the general population?

AMPD1 p.Arg75Cys (c.223C>T) is ultra-rare (popmax 0.03%, amr) (gnomAD).

What do computational predictors say about AMPD1 p.Arg75Cys (c.223C>T)?

AlphaMissense predicts likely benign (score 0.1472) — an in-silico prediction, not a clinical call.

AMPD1 p.Arg75Cys

c.223C>T · rs12566550 · VCV1440629

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1472 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.03%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

myopathy due to myoadenylate deaminase deficiency

Computational evidence

Protein change
AlphaMissense	0.1472	likely benign
REVEL	0.188	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 21 kb · p 0.9 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 R108C vs ClinVar R75C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.03% Admixed American · 18/60,010 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00235% 38/1,614,170 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.03%	3,334
East Asian	0.0156%	6,413
South Asian	0.00769%	13,011
African / African-American	0.00133%	75,048
European (non-Finnish)	0.000424%	236,005

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.Arg75Cys
Coding: c.223C>T
MANE Select: NM_000036
dbSNP: rs12566550
Type: single nucleotide variant
Location: chr1:114686903 (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.Arg75His Benign/Likely benign ★★ 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
AMPD1 p.Ala489Thr Uncertain significance ★★ ⚠ same condition
AMPD1 p.Ala578Thr 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-arg75cys (accessed [today's date]).

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