Is PEX12 p.Ser19Pro (c.55T>C) pathogenic?

PEX12 p.Ser19Pro (c.55T>C) is classified Uncertain significance in PEX12 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-08). AlphaMissense: likely pathogenic (0.9218); Very rare (popmax 0.00668%, eas); Associated with peroxisome biogenesis disorder 3A (Zellweger).

What condition is associated with PEX12 p.Ser19Pro (c.55T>C)?

PEX12 p.Ser19Pro (c.55T>C) is associated with peroxisome biogenesis disorder 3A (Zellweger) (ClinVar).

How common is PEX12 p.Ser19Pro (c.55T>C) in the general population?

PEX12 p.Ser19Pro (c.55T>C) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about PEX12 p.Ser19Pro (c.55T>C)?

AlphaMissense predicts likely pathogenic (score 0.9218) — an in-silico prediction, not a clinical call.

PEX12 p.Ser19Pro

c.55T>C · rs756812775 · VCV1389585

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9218 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

peroxisome biogenesis disorder 3A (Zellweger)

Computational evidence

Protein change
AlphaMissense	0.9218	likely pathogenic · top 10% in PEX12
REVEL	0.654	pathogenic-leaning
SaProt	LLR -10.81	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.5	phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 2,236 bp · p 0.0034 · regional, not allelic
Overall
CADD	26.5	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 0.00668% East Asian · 3/44,888 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000682% 11/1,614,044 alleles · very rare exomes 8/1,461,874 · genomes 3/152,170 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,963
South Asian	0.00659%	15,181
Remaining individualsnot grpmax-eligible	0.0032%	31,244

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.Ser19Pro
Coding: c.55T>C
MANE Select: NM_000286
dbSNP: rs756812775
Type: single nucleotide variant
Location: chr17:35577967 (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-ser19pro (accessed [today's date]).

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