Is PEX1 p.Arg985His (c.2954G>A) pathogenic?

PEX1 p.Arg985His (c.2954G>A) is classified Uncertain significance in PEX1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-10-10). AlphaMissense: likely pathogenic (0.6738); Ultra-rare (popmax 0.0329%, mid); Associated with Inborn genetic diseases.

What condition is associated with PEX1 p.Arg985His (c.2954G>A)?

PEX1 p.Arg985His (c.2954G>A) is associated with Inborn genetic diseases, peroxisome biogenesis disorder 1A (Zellweger), Zellweger spectrum disorders (ClinVar).

How common is PEX1 p.Arg985His (c.2954G>A) in the general population?

PEX1 p.Arg985His (c.2954G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about PEX1 p.Arg985His (c.2954G>A)?

AlphaMissense predicts likely pathogenic (score 0.6738) — an in-silico prediction, not a clinical call.

PEX1 p.Arg985His

c.2954G>A · rs202057449 · VCV911570

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.6738 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6738	likely pathogenic
REVEL	0.878	moderately pathogenic-leaning
SaProt	LLR -11.87	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.7	GERP 3.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 41 kb · p 4.3e-05 · regional, not allelic
Overall
CADD	33.0	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 0.0329% Middle Eastern · 2/6,080 alleles

Filtering AF 0.00901% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00842%

Overall 0.00923% 149/1,613,676 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,040
Remaining individualsnot grpmax-eligible	0.0144%	6,940
Admixed American	0.0133%	7,494
European (non-Finnish)	0.0105%	9,515
African / African-American	0.00401%	24,949
South Asian	0.00329%	30,356

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.Arg985His
Coding: c.2954G>A
MANE Select: NM_021167 · reported on NM_000466
dbSNP: rs202057449
Type: single nucleotide variant
Location: chr7:92494369 (GRCh38)

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: peroxisome biogenesis disorder 1A (Zellweger)Zellweger spectrum disorders

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-arg985his (accessed [today's date]).

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