Is PPOX p.Pro121Thr (c.361C>A) pathogenic?

PPOX p.Pro121Thr (c.361C>A) is classified Uncertain significance in PPOX (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-28). AlphaMissense: likely pathogenic (0.5756); Ultra-rare (popmax 0.0334%, eas).

How common is PPOX p.Pro121Thr (c.361C>A) in the general population?

PPOX p.Pro121Thr (c.361C>A) is ultra-rare (popmax 0.0334%, eas) (gnomAD).

What do computational predictors say about PPOX p.Pro121Thr (c.361C>A)?

AlphaMissense predicts likely pathogenic (score 0.5756) — an in-silico prediction, not a clinical call.

PPOX p.Pro121Thr

c.361C>A · rs532136485 · VCV1002893

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5756 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5756	likely pathogenic
REVEL	0.836	moderately pathogenic-leaning
SaProt	LLR -14.92	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Overall
CADD	25.6	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 0.0334% East Asian · 15/44,872 alleles

Filtering AF 0.0206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0166%

Overall 0.00105% 17/1,614,182 alleles · ultra-rare exomes 12/1,461,892 · genomes 5/152,290 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0334%	2,991
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	8.47e-05%	1,180,034

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.Pro121Thr
Coding: c.361C>A
MANE Select: NM_001122764
dbSNP: rs532136485
Type: single nucleotide variant
Location: chr1:161168017 (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

Similar variants

PPOX p.Pro121Ala Uncertain significance ★ ⚠ same residue
PPOX p.Pro121Arg Uncertain significance ★ ⚠ same residue
PPOX p.Pro121His Uncertain significance ★ ⚠ same residue
PPOX p.Pro121fs Likely pathogenic ★ same residue
PPOX c.-9G>A Likely pathogenic ★★ same type
PPOX p.Arg168His Pathogenic/Likely pathogenic ★★ ⚠ same type
PPOX p.Arg59Trp Pathogenic ★★ same type
PPOX p.Gln189Ter Pathogenic ★★ same type

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-pro121thr (accessed [today's date]).

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