Is PEX12 p.Pro49Ala (c.145C>G) pathogenic?

PEX12 p.Pro49Ala (c.145C>G) is classified Uncertain significance in PEX12 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-10). AlphaMissense: ambiguous (0.4147); Absent from gnomAD v4.1; Associated with peroxisome biogenesis disorder 3A (Zellweger).

What condition is associated with PEX12 p.Pro49Ala (c.145C>G)?

PEX12 p.Pro49Ala (c.145C>G) is associated with peroxisome biogenesis disorder 3A (Zellweger) (ClinVar).

How common is PEX12 p.Pro49Ala (c.145C>G) in the general population?

PEX12 p.Pro49Ala (c.145C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PEX12 p.Pro49Ala (c.145C>G)?

AlphaMissense predicts ambiguous (score 0.4147) — an in-silico prediction, not a clinical call.

PEX12 p.Pro49Ala

c.145C>G · rs2142231256 · VCV1409555

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4147 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

peroxisome biogenesis disorder 3A (Zellweger)

Computational evidence

Protein change
AlphaMissense	0.4147	ambiguous
REVEL	0.861	moderately pathogenic-leaning
SaProt	LLR -9.21	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 2,236 bp · p 0.0034 · regional, not allelic
Overall
CADD	27.1	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

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.Pro49Ala
Coding: c.145C>G
MANE Select: NM_000286
dbSNP: rs2142231256
Type: single nucleotide variant
Location: chr17:35577573 (GRCh38)
Gene constraint: LOEUF 1.218 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.58

Full PEX12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

peroxisome biogenesis disorder 3A (Zellweger) — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PEX12 c.126+1G>T Pathogenic/Likely pathogenic ★★ same condition
PEX12 c.680+1G>A Pathogenic/Likely pathogenic ★★ same condition
PEX12 p.Arg154Ter Pathogenic/Likely pathogenic ★★ same condition
PEX12 p.Arg180Ter Pathogenic ★★ same condition
PEX12 p.Arg202Ter Pathogenic/Likely pathogenic ★★ same condition
PEX12 p.Gln111Ter Pathogenic/Likely pathogenic ★★ same condition
PEX12 p.Gln112Ter Pathogenic/Likely pathogenic ★★ same condition
PEX12 p.Gln209Ter Pathogenic ★★ 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-pro49ala (accessed [today's date]).

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