Is PPA2 p.Leu8Arg (c.23T>G) pathogenic?

PPA2 p.Leu8Arg (c.23T>G) is classified Uncertain significance in PPA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-23). AlphaMissense: likely benign (0.0784); Very rare (popmax 0.00616%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PPA2 p.Leu8Arg (c.23T>G)?

PPA2 p.Leu8Arg (c.23T>G) is associated with Inborn genetic diseases (ClinVar).

How common is PPA2 p.Leu8Arg (c.23T>G) in the general population?

PPA2 p.Leu8Arg (c.23T>G) is very rare (popmax 0.00616%, nfe) (gnomAD).

What do computational predictors say about PPA2 p.Leu8Arg (c.23T>G)?

AlphaMissense predicts likely benign (score 0.0784) — an in-silico prediction, not a clinical call.

PPA2 p.Leu8Arg

c.23T>G · rs754626127 · VCV2066742

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0784 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00616%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0784	likely benign
REVEL	0.173	moderately benign-leaning
SaProt	LLR -9.53	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 3.9	GERP -1.7, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 104 kb · p 0.35 · regional, not allelic
Overall
CADD	12.4	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 0.00616% European (non-Finnish) · 72/1,169,724 alleles

Filtering AF 0.00499% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00459%

Overall 0.00477% 76/1,592,544 alleles · very rare exomes 69/1,440,428 · genomes 7/152,116 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00616%	16,246
African / African-American	0.00405%	24,693
Finnishnot grpmax-eligible	0.00165%	60,740

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.Leu8Arg
Coding: c.23T>G
MANE Select: NM_176869
dbSNP: rs754626127
Type: single nucleotide variant
Location: chr4:105474028 (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

PPA2 p.Leu8= Likely benign ★ same residue
PPA2 p.Ala12Val Uncertain significance ★★ ⚠ same condition
PPA2 p.Ala16Val Uncertain significance ★★ ⚠ same condition
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

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-leu8arg (accessed [today's date]).

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