Is PEX6 p.Pro17Ser (c.49C>T) pathogenic?

PEX6 p.Pro17Ser (c.49C>T) is classified Uncertain significance in PEX6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-10). AlphaMissense: likely benign (0.0844); Very rare (popmax 8.6e-05%, nfe); Associated with PEX6-related disorder.

What condition is associated with PEX6 p.Pro17Ser (c.49C>T)?

PEX6 p.Pro17Ser (c.49C>T) is associated with PEX6-related disorder (ClinVar).

How common is PEX6 p.Pro17Ser (c.49C>T) in the general population?

PEX6 p.Pro17Ser (c.49C>T) is very rare (popmax 8.6e-05%, nfe) (gnomAD).

What do computational predictors say about PEX6 p.Pro17Ser (c.49C>T)?

AlphaMissense predicts likely benign (score 0.0844) — an in-silico prediction, not a clinical call.

PEX6 p.Pro17Ser

c.49C>T · rs918969564 · VCV2372268

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0844 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.6e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PEX6-related disorder

Computational evidence

Protein change
AlphaMissense	0.0844	likely benign
REVEL	0.238	benign-leaning
SaProt	LLR -6.29	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP -2, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 10 kb · p 0.19 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.6e-05% European (non-Finnish) · 1/1,162,342 alleles

Overall 6.4e-05% 1/1,561,494 alleles · very rare exomes 1/1,409,184 · genomes 0/152,310 · 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.Pro17Ser
Coding: c.49C>T
MANE Select: NM_000287
dbSNP: rs918969564
Type: single nucleotide variant
Location: chr6:42979102 (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

PEX6-related disorder

Similar variants

PEX6 p.Pro17Thr Uncertain significance ★★ ⚠ same residue
PEX6 c.2095-2A>G Likely pathogenic ★★ same condition
PEX6 p.Arg860Gln Likely pathogenic ★★ same condition
PEX6 p.Arg860Trp Pathogenic/Likely pathogenic ★★ same condition
PEX6 p.Leu57Pro Likely pathogenic ★★ ⚠ same condition
PEX6 p.Pro274Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
PEX6 p.Val97Gly Pathogenic/Likely pathogenic ★★ ⚠ same condition
PEX6 p.Arg536Gln Uncertain significance ★★ ⚠ 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-pro17ser (accessed [today's date]).

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