Is PPA2 p.His218Arg (c.653A>G) pathogenic?

PPA2 p.His218Arg (c.653A>G) is classified Uncertain significance in PPA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-27). AlphaMissense: likely benign (0.0828); Very rare (popmax 0.00225%, eas); Associated with Inborn genetic diseases.

What condition is associated with PPA2 p.His218Arg (c.653A>G)?

PPA2 p.His218Arg (c.653A>G) is associated with Inborn genetic diseases (ClinVar).

How common is PPA2 p.His218Arg (c.653A>G) in the general population?

PPA2 p.His218Arg (c.653A>G) is very rare (popmax 0.00225%, eas) (gnomAD).

What do computational predictors say about PPA2 p.His218Arg (c.653A>G)?

AlphaMissense predicts likely benign (score 0.0828) — an in-silico prediction, not a clinical call.

PPA2 p.His218Arg

c.653A>G · rs746773886 · VCV1354163

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0828 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00225%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0828	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	LLR -9.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 104 kb · p 0.35 · regional, not allelic
Overall
CADD	19.03	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00225% East Asian · 1/44,418 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000375% 6/1,601,120 alleles · very rare exomes 5/1,448,902 · genomes 1/152,218 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00316%	31,625
East Asiangrpmax	0.00225%	44,418
South Asian	0.00114%	87,592
European (non-Finnish)	0.00017%	588,582

Finnish 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: PPA2
Protein: p.His218Arg
Coding: c.653A>G
MANE Select: NM_176869
dbSNP: rs746773886
Type: single nucleotide variant
Location: chr4:105424198 (GRCh38)
Gene constraint: LOEUF 1.324 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.39

Full PPA2 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

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PPA2 p.Arg9Leu Uncertain significance ★★ ⚠ same condition
PPA2 p.Asn260Ser Uncertain significance ★★ ⚠ same condition
PPA2 p.Asn319Tyr Uncertain significance ★★ ⚠ same condition
PPA2 p.Asp156Tyr Uncertain significance ★★ ⚠ same condition
PPA2 p.Asp245Asn Uncertain significance ★★ ⚠ same condition
PPA2 p.Gln251Leu 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/ppa2-p-his218arg (accessed [today's date]).

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