Is AMPD2 p.Arg213His (c.638G>A) pathogenic?

AMPD2 p.Arg213His (c.638G>A) is classified Uncertain significance in AMPD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely benign (0.083); Ultra-rare (popmax 0.0133%, amr); Associated with Inborn genetic diseases.

What condition is associated with AMPD2 p.Arg213His (c.638G>A)?

AMPD2 p.Arg213His (c.638G>A) is associated with Inborn genetic diseases (ClinVar).

How common is AMPD2 p.Arg213His (c.638G>A) in the general population?

AMPD2 p.Arg213His (c.638G>A) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about AMPD2 p.Arg213His (c.638G>A)?

AlphaMissense predicts likely benign (score 0.083) — an in-silico prediction, not a clinical call.

AMPD2 p.Arg213His

c.638G>A · VCV4092931

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.083 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.083	likely benign
REVEL	0.084	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 8.6	GERP -1.4, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,721 bp · p 0.065 · regional, not allelic
Overall
CADD	25.1	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 R267H vs ClinVar R213H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% Admixed American · 8/59,988 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.00161% 26/1,613,694 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,499
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,793
Remaining individualsnot grpmax-eligible	0.0032%	31,235
East Asian	0.00223%	44,876
Finnishnot grpmax-eligible	0.00157%	63,882
South Asian	0.0011%	91,090
European (non-Finnish)	0.000932%	107,266

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.Arg213His
Coding: c.638G>A
MANE Select: NM_001368809
Type: single nucleotide variant
Location: chr1:109626832 (GRCh38)
Gene constraint: LOEUF 0.705 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.28 · 5 PDB
Residue 213: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AMPD2 c.-150G>A Uncertain significance ★★ ⚠ same condition
AMPD2 c.-18G>T Uncertain significance ★★ ⚠ same condition
AMPD2 p.Ala425= Uncertain significance ★★ same condition
AMPD2 p.Arg156Gln Uncertain significance ★★ ⚠ same condition
AMPD2 p.Arg163Gln Uncertain significance ★★ ⚠ same condition
AMPD2 p.Arg386Trp Uncertain significance ★★ same condition
AMPD2 p.Asn746Ser Uncertain significance ★★ ⚠ same condition
AMPD2 p.Asp60Asn 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/ampd2-p-arg213his (accessed [today's date]).

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