Is PEX6 p.Glu221Ter (c.661G>T) pathogenic?

PEX6 p.Glu221Ter (c.661G>T) is classified Likely pathogenic in PEX6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-21). Very rare (popmax 0.00133%, afr); Associated with Heimler syndrome 2.

What condition is associated with PEX6 p.Glu221Ter (c.661G>T)?

PEX6 p.Glu221Ter (c.661G>T) is associated with Heimler syndrome 2 (ClinVar).

How common is PEX6 p.Glu221Ter (c.661G>T) in the general population?

PEX6 p.Glu221Ter (c.661G>T) is very rare (popmax 0.00133%, afr) (gnomAD).

PEX6 p.Glu221Ter

c.661G>T · rs786205580 · VCV191209

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

Heimler syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 17
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,052 alleles

Overall 6.2e-05% 1/1,614,194 alleles · very rare exomes 1/1,461,880 · genomes 0/152,314 · joint denominator

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.Glu221Ter
Coding: c.661G>T
MANE Select: NM_000287
dbSNP: rs786205580
Type: single nucleotide variant
Location: chr6:42978490 (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

Heimler syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PEX6 p.Glu221= Likely benign ★ same residue
PEX6 p.Glu221Lys Likely benign same residue
PEX6 c.1233+1G>A Likely pathogenic ★★ same condition
PEX6 c.2094+1G>A Likely pathogenic ★★ same condition
PEX6 c.2300+2T>C Likely pathogenic ★★ same condition
PEX6 c.2666+1G>T Likely pathogenic ★★ same condition
PEX6 c.2807-2A>G Pathogenic/Likely pathogenic ★★ same condition
PEX6 p.Cys358Ter 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-glu221ter (accessed [today's date]).

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