Is PEX12 p.Ser320Phe (c.959C>T) pathogenic?

PEX12 p.Ser320Phe (c.959C>T) is classified Pathogenic/Likely pathogenic in PEX12 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2024-03-26). AlphaMissense: likely pathogenic (0.9938); Ultra-rare (popmax 0.0165%, mid); Associated with peroxisome biogenesis disorder 3A (Zellweger).

What condition is associated with PEX12 p.Ser320Phe (c.959C>T)?

PEX12 p.Ser320Phe (c.959C>T) is associated with peroxisome biogenesis disorder 3A (Zellweger), peroxisome biogenesis disorder type 3B, peroxisome biogenesis disorder (ClinVar).

How common is PEX12 p.Ser320Phe (c.959C>T) in the general population?

PEX12 p.Ser320Phe (c.959C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about PEX12 p.Ser320Phe (c.959C>T)?

AlphaMissense predicts likely pathogenic (score 0.9938) — an in-silico prediction, not a clinical call.

PEX12 p.Ser320Phe

c.959C>T · rs28936697 · VCV7775

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9938 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

peroxisome biogenesis disorder 3A (Zellweger)

Computational evidence

Protein change
AlphaMissense	0.9938	likely pathogenic ✓ concordant with ClinVar · top 1% in PEX12
REVEL	0.921	moderately pathogenic-leaning
SaProt	LLR -10.42	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 11	phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 2,236 bp · p 0.0034 · regional, not allelic
Overall
CADD	33.0	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000372% 6/1,614,238 alleles · ultra-rare exomes 6/1,461,884 · genomes 0/152,354 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	0.000339%	295,010

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.Ser320Phe
Coding: c.959C>T
MANE Select: NM_000286
dbSNP: rs28936697
Type: single nucleotide variant
Location: chr17:35575903 (GRCh38)
Gene constraint: LOEUF 1.218 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.58
Residue 320: a UniProt-annotated variant site (in pbd3a); a UniProt-annotated variant site (in pbd3b; attenuates interaction with pex10 and decreases peroxisomal protein import)

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

Also linked: peroxisome biogenesis disorder type 3B peroxisome biogenesis disorder

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-ser320phe (accessed [today's date]).

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