Is AMPD2 p.Arg508His (c.1523G>A) pathogenic?

AMPD2 p.Arg508His (c.1523G>A) is classified Uncertain significance in AMPD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-20). AlphaMissense: likely benign (0.0817); Very rare (popmax 0.0023%, eas).

How common is AMPD2 p.Arg508His (c.1523G>A) in the general population?

AMPD2 p.Arg508His (c.1523G>A) is very rare (popmax 0.0023%, eas) (gnomAD).

What do computational predictors say about AMPD2 p.Arg508His (c.1523G>A)?

AlphaMissense predicts likely benign (score 0.0817) — an in-silico prediction, not a clinical call.

AMPD2 p.Arg508His

c.1523G>A · rs982118760 · VCV2499780

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0817 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0023%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.0817	likely benign
REVEL	0.176	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 4.4	GERP -1.2, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 3,009 bp · p 8.7e-13 · regional, not allelic
Overall
CADD	23.2	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 R562H vs ClinVar R508H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0023% East Asian · 1/43,424 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000278% 4/1,438,000 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0023%	43,424
Remaining individualsnot grpmax-eligible	0.00162%	61,558
European (non-Finnish)	0.000171%	583,833

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.Arg508His
Coding: c.1523G>A
MANE Select: NM_001368809
dbSNP: rs982118760
Type: single nucleotide variant
Location: chr1:109628758 (GRCh38)
Gene constraint: LOEUF 0.705 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.28 · 5 PDB

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

Similar variants

AMPD2 p.Arg508Cys Uncertain significance ★ same residue
AMPD2 p.Arg508Gly Uncertain significance ★ ⚠ same residue
AMPD2 p.Arg508= Likely benign ★ same residue
AMPD2 c.1698+1G>A Pathogenic/Likely pathogenic ★★ same type
AMPD2 p.Arg353Ter Pathogenic/Likely pathogenic ★★ same type
AMPD2 p.Arg449Ter Pathogenic/Likely pathogenic ★★ same type
AMPD2 p.Arg620His Pathogenic/Likely pathogenic ★★ same type
AMPD2 p.Arg789His 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-arg508his (accessed [today's date]).

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