Is PPA2 p.Phe258Leu (c.772T>C) pathogenic?

PPA2 p.Phe258Leu (c.772T>C) is classified Uncertain significance in PPA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-01). AlphaMissense: likely pathogenic (0.9009); Ultra-rare (popmax 0.0112%, eas); Associated with Inborn genetic diseases.

What condition is associated with PPA2 p.Phe258Leu (c.772T>C)?

PPA2 p.Phe258Leu (c.772T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PPA2 p.Phe258Leu (c.772T>C) in the general population?

PPA2 p.Phe258Leu (c.772T>C) is ultra-rare (popmax 0.0112%, eas) (gnomAD).

What do computational predictors say about PPA2 p.Phe258Leu (c.772T>C)?

AlphaMissense predicts likely pathogenic (score 0.9009) — an in-silico prediction, not a clinical call.

PPA2 p.Phe258Leu

c.772T>C · rs778127919 · VCV3217003

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9009 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0112%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9009	likely pathogenic · top 2% in PPA2
REVEL	0.335	indeterminate
SaProt	LLR -11.70	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 104 kb · p 0.35 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0112% East Asian · 5/44,820 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000311% 5/1,608,644 alleles · ultra-rare exomes 5/1,456,374 · genomes 0/152,270 · joint denominator

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.Phe258Leu
Coding: c.772T>C
MANE Select: NM_176869
dbSNP: rs778127919
Type: single nucleotide variant
Location: chr4:105399048 (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.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
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-phe258leu (accessed [today's date]).

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