Is PEX12 p.Pro305Ala (c.913C>G) pathogenic?

PEX12 p.Pro305Ala (c.913C>G) is classified Uncertain significance in PEX12 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-14). AlphaMissense: likely benign (0.2478); Very rare (popmax 0.00333%, amr); Associated with peroxisome biogenesis disorder 3A (Zellweger).

What condition is associated with PEX12 p.Pro305Ala (c.913C>G)?

PEX12 p.Pro305Ala (c.913C>G) is associated with peroxisome biogenesis disorder 3A (Zellweger) (ClinVar).

How common is PEX12 p.Pro305Ala (c.913C>G) in the general population?

PEX12 p.Pro305Ala (c.913C>G) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about PEX12 p.Pro305Ala (c.913C>G)?

AlphaMissense predicts likely benign (score 0.2478) — an in-silico prediction, not a clinical call.

PEX12 p.Pro305Ala

c.913C>G · rs1444133628 · VCV1417663

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2478 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

peroxisome biogenesis disorder 3A (Zellweger)

Computational evidence

Protein change
AlphaMissense	0.2478	likely benign
REVEL	0.853	moderately pathogenic-leaning
SaProt	LLR -6.72	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 2,236 bp · p 0.0034 · regional, not allelic
Overall
CADD	27.0	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 0.00333% Admixed American · 2/60,016 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,614,154 alleles · very rare exomes 2/1,461,878 · genomes 0/152,276 · 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: PEX12
Protein: p.Pro305Ala
Coding: c.913C>G
MANE Select: NM_000286
dbSNP: rs1444133628
Type: single nucleotide variant
Location: chr17:35575949 (GRCh38)
Gene constraint: LOEUF 1.218 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.58
Residue 305: a UniProt-annotated variant site (in pbd3a)

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 p.Pro305Ser Uncertain significance ★ ⚠ same residue
PEX12 p.Pro305= Likely benign ★ same residue
PEX12 p.Pro305fs Likely pathogenic ★ same residue
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

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-pro305ala (accessed [today's date]).

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