Is PPOX p.Pro28Thr (c.82C>A) pathogenic?

PPOX p.Pro28Thr (c.82C>A) is classified Uncertain significance in PPOX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-11). AlphaMissense: likely benign (0.1559); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with PPOX p.Pro28Thr (c.82C>A)?

PPOX p.Pro28Thr (c.82C>A) is associated with Inborn genetic diseases (ClinVar).

How common is PPOX p.Pro28Thr (c.82C>A) in the general population?

PPOX p.Pro28Thr (c.82C>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about PPOX p.Pro28Thr (c.82C>A)?

AlphaMissense predicts likely benign (score 0.1559) — an in-silico prediction, not a clinical call.

PPOX p.Pro28Thr

c.82C>A · rs758987522 · VCV2894196

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1559 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1559	likely benign
REVEL	0.45	indeterminate
SaProt	LLR -15.40	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.4, phastCons 1
Overall
CADD	19.59	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00149% 24/1,613,876 alleles · ultra-rare exomes 22/1,461,636 · genomes 2/152,240 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
African / African-American	0.00267%	37,471
South Asian	0.0022%	45,544
Admixed American	0.00167%	60,008
European (non-Finnish)	0.00153%	65,557

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: PPOX
Protein: p.Pro28Thr
Coding: c.82C>A
MANE Select: NM_001122764
dbSNP: rs758987522
Type: single nucleotide variant
Location: chr1:161166929 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.24 (gnomAD)
Structure: AlphaFold pLDDT 95.39 · 3 PDB

Full PPOX 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

PPOX p.Pro28Ala Uncertain significance ★★ ⚠ same residue
PPOX p.Pro28Arg Uncertain significance ★ ⚠ same residue
PPOX p.Pro28Leu Uncertain significance ★ ⚠ same residue
PPOX p.Ala221Thr Uncertain significance ★★ ⚠ same condition
PPOX p.Arg152His Uncertain significance ★★ ⚠ same condition
PPOX p.Arg267Cys Uncertain significance ★★ ⚠ same condition
PPOX p.Arg3Gln Uncertain significance ★★ ⚠ same condition
PPOX p.Gln421His 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/ppox-p-pro28thr (accessed [today's date]).

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