Is PEX12 p.Leu276Ser (c.827T>C) pathogenic?

PEX12 p.Leu276Ser (c.827T>C) is classified Uncertain significance in PEX12 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-12). AlphaMissense: likely pathogenic (0.8427); Very rare (popmax 0.00267%, afr); Associated with peroxisome biogenesis disorder 3A (Zellweger).

What condition is associated with PEX12 p.Leu276Ser (c.827T>C)?

PEX12 p.Leu276Ser (c.827T>C) is associated with peroxisome biogenesis disorder 3A (Zellweger) (ClinVar).

How common is PEX12 p.Leu276Ser (c.827T>C) in the general population?

PEX12 p.Leu276Ser (c.827T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about PEX12 p.Leu276Ser (c.827T>C)?

AlphaMissense predicts likely pathogenic (score 0.8427) — an in-silico prediction, not a clinical call.

PEX12 p.Leu276Ser

c.827T>C · rs1249994630 · VCV2179231

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8427 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

peroxisome biogenesis disorder 3A (Zellweger)

Computational evidence

Protein change
AlphaMissense	0.8427	likely pathogenic
REVEL	0.594	indeterminate
SaProt	LLR -8.76	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
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	26.9	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 0.00267% African / African-American · 2/74,898 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00198% 32/1,614,018 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,449
European (non-Finnish)	0.00246%	40,691
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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.Leu276Ser
Coding: c.827T>C
MANE Select: NM_000286
dbSNP: rs1249994630
Type: single nucleotide variant
Location: chr17:35576035 (GRCh38)
Gene constraint: LOEUF 1.218 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.58
Residue 276: 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.Leu276= Likely benign ★ 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
PEX12 p.Gln111Ter Pathogenic/Likely pathogenic ★★ same condition
PEX12 p.Gln112Ter 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-leu276ser (accessed [today's date]).

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