Is PEX1 p.Ile414Val (c.1240A>G) pathogenic?

PEX1 p.Ile414Val (c.1240A>G) is classified Uncertain significance in PEX1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-15). AlphaMissense: likely benign (0.2018); Ultra-rare (popmax 0.0136%, amr); Associated with Inborn genetic diseases.

What condition is associated with PEX1 p.Ile414Val (c.1240A>G)?

PEX1 p.Ile414Val (c.1240A>G) is associated with Inborn genetic diseases, Zellweger spectrum disorders (ClinVar).

How common is PEX1 p.Ile414Val (c.1240A>G) in the general population?

PEX1 p.Ile414Val (c.1240A>G) is ultra-rare (popmax 0.0136%, amr) (gnomAD).

What do computational predictors say about PEX1 p.Ile414Val (c.1240A>G)?

AlphaMissense predicts likely benign (score 0.2018) — an in-silico prediction, not a clinical call.

PEX1 p.Ile414Val

c.1240A>G · rs759491353 · VCV596776

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2018 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0136%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2018	likely benign
REVEL	0.337	indeterminate
SaProt	LLR -7.63	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 4.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 41 kb · p 4.3e-05 · regional, not allelic
Overall
CADD	21.9	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 0.0136% Admixed American · 8/58,918 alleles

Filtering AF 0.00672% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0049%

Overall 0.000577% 9/1,560,048 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0136%	7,365
Remaining individualsnot grpmax-eligible	0.00165%	60,610

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: PEX1
Protein: p.Ile414Val
Coding: c.1240A>G
MANE Select: NM_000466
dbSNP: rs759491353
Type: single nucleotide variant
Location: chr7:92513967 (GRCh38)
Gene constraint: LOEUF 0.746 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.19

Full PEX1 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

Also linked: Zellweger spectrum disorders

Similar variants

PEX1 c.1239+1G>T Pathogenic ★★ same condition
PEX1 c.130-1G>T Pathogenic/Likely pathogenic ★★ same condition
PEX1 c.130-2A>G Pathogenic/Likely pathogenic ★★ same condition
PEX1 c.130-2A>T Pathogenic/Likely pathogenic ★★ same condition
PEX1 c.1483+1G>A Pathogenic ★★ same condition
PEX1 c.1587+1G>A Likely pathogenic ★★ same condition
PEX1 c.1670+1G>A Pathogenic/Likely pathogenic ★★ same condition
PEX1 c.1670+1G>T 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/pex1-p-ile414val (accessed [today's date]).

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