Is PEX6 p.Leu112Pro (c.335T>C) pathogenic?

PEX6 p.Leu112Pro (c.335T>C) is classified Likely benign in PEX6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-22). AlphaMissense: likely benign (0.0389); Very rare (popmax 0.00119%, sas); Associated with Inborn genetic diseases.

What condition is associated with PEX6 p.Leu112Pro (c.335T>C)?

PEX6 p.Leu112Pro (c.335T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PEX6 p.Leu112Pro (c.335T>C) in the general population?

PEX6 p.Leu112Pro (c.335T>C) is very rare (popmax 0.00119%, sas) (gnomAD).

What do computational predictors say about PEX6 p.Leu112Pro (c.335T>C)?

AlphaMissense predicts likely benign (score 0.0389) — an in-silico prediction, not a clinical call.

PEX6 p.Leu112Pro

c.335T>C · rs1397437694 · VCV2234153

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0389 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0389	likely benign
REVEL	0.178	moderately benign-leaning
SaProt	LLR -5.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.4	GERP 0.53, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 10 kb · p 0.19 · regional, not allelic
Overall
CADD	18.37	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 0.00119% South Asian · 1/83,928 alleles

Overall 6.52e-05% 1/1,533,226 alleles · very rare exomes 1/1,381,106 · genomes 0/152,120 · 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.Leu112Pro
Coding: c.335T>C
MANE Select: NM_000287
dbSNP: rs1397437694
Type: single nucleotide variant
Location: chr6:42978816 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PEX6 p.Leu112= Likely benign ★ same residue
PEX6 p.Ala240Gly Uncertain significance ★★ ⚠ same condition
PEX6 p.Ala2Thr Uncertain significance ★★ ⚠ same condition
PEX6 p.Ala51Glu Uncertain significance ★★ ⚠ same condition
PEX6 p.Ala581Thr Uncertain significance ★★ ⚠ same condition
PEX6 p.Arg209Trp Uncertain significance ★★ ⚠ same condition
PEX6 p.Arg229Lys Uncertain significance ★★ ⚠ same condition
PEX6 p.Arg469Gln 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-leu112pro (accessed [today's date]).

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