Is PEX6 p.Ala912= (c.2736G>A) pathogenic?

PEX6 p.Ala912= (c.2736G>A) is classified Conflicting classifications of pathogenicity in PEX6 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-22). Ultra-rare (popmax 0.0357%, eas); Associated with peroxisome biogenesis disorder 4A (Zellweger).

What condition is associated with PEX6 p.Ala912= (c.2736G>A)?

PEX6 p.Ala912= (c.2736G>A) is associated with peroxisome biogenesis disorder 4A (Zellweger), peroxisome biogenesis disorder, Zellweger spectrum disorders (ClinVar).

How common is PEX6 p.Ala912= (c.2736G>A) in the general population?

PEX6 p.Ala912= (c.2736G>A) is ultra-rare (popmax 0.0357%, eas) (gnomAD).

PEX6 p.Ala912=

c.2736G>A · rs202049230 · VCV356794

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0357%, eas)

Conditions

peroxisome biogenesis disorder 4A (Zellweger)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -5.6	GERP -3.1
Overall
CADD	2.894	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0357% East Asian · 16/44,880 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.00341% 55/1,614,054 alleles · ultra-rare exomes 50/1,461,848 · genomes 5/152,206 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0357%	2,805
South Asian	0.0154%	6,505
African / African-American	0.00533%	18,750
Admixed American	0.00333%	30,002
European (non-Finnish)	0.00161%	62,104

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: PEX6
Protein: p.Ala912=
Coding: c.2736G>A
MANE Select: NM_000287
dbSNP: rs202049230
Type: single nucleotide variant
Location: chr6:42964860 (GRCh38)
Gene constraint: LOEUF 0.799 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.87

Full PEX6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

peroxisome biogenesis disorder 4A (Zellweger) — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: peroxisome biogenesis disorder Zellweger spectrum disorders

Similar variants

PEX6 p.Ala912Thr Pathogenic/Likely pathogenic ★★ same residue
PEX6 p.Ala912Val Pathogenic/Likely pathogenic ★★ same residue
PEX6 p.Ala912Ser Uncertain significance ★ ⚠ same residue
PEX6 c.1130+1G>A Likely pathogenic ★★ same condition
PEX6 c.1233+1G>A Likely pathogenic ★★ same condition
PEX6 c.1688+1G>A Pathogenic ★★ same condition
PEX6 c.1689-1G>A Likely pathogenic ★★ same condition
PEX6 c.1885-1G>A 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/pex6-p-ala912 (accessed [today's date]).

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