Is PEX6 p.Ala693Asp (c.2078C>A) pathogenic?

PEX6 p.Ala693Asp (c.2078C>A) is classified Conflicting classifications of pathogenicity in PEX6 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-22). AlphaMissense: likely benign (0.2549); Ultra-rare (popmax 0.08%, amr); Associated with peroxisome biogenesis disorder.

What condition is associated with PEX6 p.Ala693Asp (c.2078C>A)?

PEX6 p.Ala693Asp (c.2078C>A) is associated with peroxisome biogenesis disorder, Zellweger spectrum disorders (ClinVar).

How common is PEX6 p.Ala693Asp (c.2078C>A) in the general population?

PEX6 p.Ala693Asp (c.2078C>A) is ultra-rare (popmax 0.08%, amr) (gnomAD).

What do computational predictors say about PEX6 p.Ala693Asp (c.2078C>A)?

AlphaMissense predicts likely benign (score 0.2549) — an in-silico prediction, not a clinical call.

PEX6 p.Ala693Asp

c.2078C>A · rs748535121 · VCV500963

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2549 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.08%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

peroxisome biogenesis disorder

Computational evidence

Protein change
AlphaMissense	0.2549	likely benign
REVEL	0.734	pathogenic-leaning
SaProt	LLR -11.29	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.66 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 4,158 bp · p 6.4e-06 · regional, not allelic
Overall
CADD	25.4	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 0.08% Admixed American · 48/60,000 alleles

Filtering AF 0.0619% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0555%

Overall 0.00316% 51/1,614,042 alleles · ultra-rare exomes 50/1,461,890 · genomes 1/152,152 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.08%	1,250
Remaining individualsnot grpmax-eligible	0.0048%	20,830

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.Ala693Asp
Coding: c.2078C>A
MANE Select: NM_000287
dbSNP: rs748535121
Type: single nucleotide variant
Location: chr6:42966541 (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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Zellweger spectrum disorders

Similar variants

PEX6 p.Ala693= Likely benign ★ 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
PEX6 c.1962-1G>A Pathogenic/Likely pathogenic ★★ same condition
PEX6 c.2094+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-ala693asp (accessed [today's date]).

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