Is PEX1 p.Arg419Lys (c.1256G>A) pathogenic?

PEX1 p.Arg419Lys (c.1256G>A) is classified Uncertain significance in PEX1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-18). AlphaMissense: ambiguous (0.3873); Ultra-rare (popmax 0.0121%, afr).

How common is PEX1 p.Arg419Lys (c.1256G>A) in the general population?

PEX1 p.Arg419Lys (c.1256G>A) is ultra-rare (popmax 0.0121%, afr) (gnomAD).

What do computational predictors say about PEX1 p.Arg419Lys (c.1256G>A)?

AlphaMissense predicts ambiguous (score 0.3873) — an in-silico prediction, not a clinical call.

PEX1 p.Arg419Lys

c.1256G>A · rs748937542 · VCV285507

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3873 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3873	ambiguous
REVEL	0.67	pathogenic-leaning
SaProt	LLR -10.06	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 3.2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 41 kb · p 4.3e-05 · regional, not allelic
Overall
CADD	24.3	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 0.0121% African / African-American · 9/74,078 alleles

Filtering AF 0.0063% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00472%

Overall 0.000699% 11/1,572,580 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0121%	8,231
South Asian	0.00113%	88,416
European (non-Finnish)	8.73e-05%	1,145,832

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.Arg419Lys
Coding: c.1256G>A
MANE Select: NM_000466
dbSNP: rs748937542
Type: single nucleotide variant
Location: chr7:92513951 (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

Similar variants

PEX1 c.1239+1G>T Pathogenic ★★ same type
PEX1 c.130-1G>T Pathogenic/Likely pathogenic ★★ same type
PEX1 c.130-2A>G Pathogenic/Likely pathogenic ★★ same type
PEX1 c.130-2A>T Pathogenic/Likely pathogenic ★★ same type
PEX1 c.1483+1G>A Pathogenic ★★ same type
PEX1 c.1587+1G>A Likely pathogenic ★★ same type
PEX1 c.1670+1G>A Pathogenic/Likely pathogenic ★★ same type
PEX1 c.1670+1G>T 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/pex1-p-arg419lys (accessed [today's date]).

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