Is PEX12 p.Pro280Arg (c.839C>G) pathogenic?

PEX12 p.Pro280Arg (c.839C>G) is classified Uncertain significance in PEX12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely pathogenic (0.7429); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PEX12 p.Pro280Arg (c.839C>G)?

PEX12 p.Pro280Arg (c.839C>G) is associated with Inborn genetic diseases (ClinVar).

How common is PEX12 p.Pro280Arg (c.839C>G) in the general population?

PEX12 p.Pro280Arg (c.839C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PEX12 p.Pro280Arg (c.839C>G)?

AlphaMissense predicts likely pathogenic (score 0.7429) — an in-silico prediction, not a clinical call.

PEX12 p.Pro280Arg

c.839C>G · VCV4134886

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7429 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7429	likely pathogenic
REVEL	0.788	moderately pathogenic-leaning
SaProt	LLR -11.60	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 9.6	phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 2,236 bp · p 0.0034 · regional, not allelic
Overall
CADD	28.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PEX12
Protein: p.Pro280Arg
Coding: c.839C>G
MANE Select: NM_000286
Type: single nucleotide variant
Location: chr17:35576023 (GRCh38)
Gene constraint: LOEUF 1.218 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.58
Residue 280: a UniProt-annotated variant site (in pbd3a)

Full PEX12 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

PEX12 p.Pro280His Uncertain significance ★ ⚠ same residue
PEX12 p.Ala338Thr Uncertain significance ★★ ⚠ same condition
PEX12 p.Asn291Thr Uncertain significance ★★ ⚠ same condition
PEX12 p.Asp16Asn Uncertain significance ★★ ⚠ same condition
PEX12 p.Glu139Lys Uncertain significance ★★ same condition
PEX12 p.Glu3Gly Uncertain significance ★★ same condition
PEX12 p.Gly242Ser Uncertain significance ★★ ⚠ same condition
PEX12 p.Ile341Phe 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/pex12-p-pro280arg (accessed [today's date]).

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