Is PEX6 p.Pro746Ser (c.2236C>T) pathogenic?

PEX6 p.Pro746Ser (c.2236C>T) is classified Uncertain significance in PEX6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-23). AlphaMissense: likely pathogenic (0.7706); Very rare (popmax 0.00223%, eas).

How common is PEX6 p.Pro746Ser (c.2236C>T) in the general population?

PEX6 p.Pro746Ser (c.2236C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about PEX6 p.Pro746Ser (c.2236C>T)?

AlphaMissense predicts likely pathogenic (score 0.7706) — an in-silico prediction, not a clinical call.

PEX6 p.Pro746Ser

c.2236C>T · rs1203501462 · VCV2430659

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7706 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7706	likely pathogenic
REVEL	0.823	moderately pathogenic-leaning
SaProt	LLR -13.53	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 4,158 bp · p 6.4e-06 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00223% East Asian · 1/44,878 alleles

Overall 0.000124% 2/1,612,916 alleles · very rare exomes 2/1,460,620 · genomes 0/152,296 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,878
Admixed American	0.00167%	60,022

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.Pro746Ser
Coding: c.2236C>T
MANE Select: NM_000287
dbSNP: rs1203501462
Type: single nucleotide variant
Location: chr6:42966306 (GRCh38)
Gene constraint: LOEUF 0.799 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.87
Residue 746: a binding site

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

Similar variants

PEX6 p.Pro746fs Likely pathogenic ★ same residue
PEX6 c.1130+1G>A Likely pathogenic ★★ same type
PEX6 c.1233+1G>A Likely pathogenic ★★ same type
PEX6 c.1688+1G>A Pathogenic ★★ same type
PEX6 c.1689-1G>A Likely pathogenic ★★ same type
PEX6 c.1885-1G>A Likely pathogenic ★★ same type
PEX6 c.1961+1G>A Likely pathogenic ★★ same type
PEX6 c.1962-1G>A Pathogenic/Likely pathogenic ★★ same type

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-pro746ser (accessed [today's date]).

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