Is AMPD1 p.Arg75His (c.224G>A) pathogenic?

AMPD1 p.Arg75His (c.224G>A) is classified Benign/Likely benign in AMPD1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0993); Low-frequency (popmax 1.63%, mid); Associated with myopathy due to myoadenylate deaminase deficiency.

What condition is associated with AMPD1 p.Arg75His (c.224G>A)?

AMPD1 p.Arg75His (c.224G>A) is associated with myopathy due to myoadenylate deaminase deficiency (ClinVar).

How common is AMPD1 p.Arg75His (c.224G>A) in the general population?

AMPD1 p.Arg75His (c.224G>A) is low-frequency (popmax 1.63%, mid) (gnomAD).

What do computational predictors say about AMPD1 p.Arg75His (c.224G>A)?

AlphaMissense predicts likely benign (score 0.0993) — an in-silico prediction, not a clinical call.

AMPD1 p.Arg75His

c.224G>A · rs61738827 · VCV166684

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0993 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.63%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

myopathy due to myoadenylate deaminase deficiency

Computational evidence

Protein change
AlphaMissense	0.0993	likely benign
REVEL	0.093	moderately 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 1.8	GERP 0.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 21 kb · p 0.9 · regional, not allelic
Overall
CADD	20.5	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 R108H vs ClinVar R75H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.63% Middle Eastern · 99/6,062 alleles

Filtering AF 1.37% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.28%

Overall 0.38% 6,129/1,614,150 alleles · low-frequency

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	2.32%	43
Middle Easterngrpmax	1.63%	61
South Asian	1.23%	82
Remaining individualsnot grpmax-eligible	0.555%	180
Admixed American	0.347%	289
European (non-Finnish)	0.302%	331
Amishnot grpmax-eligible	0.11%	912
African / African-American	0.0986%	1,014
Finnishnot grpmax-eligible	0.0422%	2,371
East Asian	0.0111%	8,977

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg75His
Coding: c.224G>A
MANE Select: NM_000036
dbSNP: rs61738827
Type: single nucleotide variant
Location: chr1:114686902 (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.Arg75Cys 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
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-arg75his (accessed [today's date]).

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