Is PEX3 p.Lys149Arg (c.446A>G) pathogenic?

PEX3 p.Lys149Arg (c.446A>G) is classified Uncertain significance in PEX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-28). AlphaMissense: likely benign (0.0672); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with PEX3 p.Lys149Arg (c.446A>G)?

PEX3 p.Lys149Arg (c.446A>G) is associated with Inborn genetic diseases (ClinVar).

How common is PEX3 p.Lys149Arg (c.446A>G) in the general population?

PEX3 p.Lys149Arg (c.446A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about PEX3 p.Lys149Arg (c.446A>G)?

AlphaMissense predicts likely benign (score 0.0672) — an in-silico prediction, not a clinical call.

PEX3 p.Lys149Arg

c.446A>G · VCV4627302

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0672 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0672	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -6.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP -2.1, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 38 kb · p 8.4e-05 · regional, not allelic
Overall
CADD	17.34	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 0.00167% Admixed American · 1/60,022 alleles

Overall 0.000124% 2/1,613,616 alleles · very rare exomes 2/1,461,284 · genomes 0/152,332 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,022
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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: PEX3
Protein: p.Lys149Arg
Coding: c.446A>G
MANE Select: NM_003630
Type: single nucleotide variant
Location: chr6:143471075 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 88.94 · 2 PDB
Residue 149: a β-strand

Full PEX3 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

PEX3 p.Ala358Val Uncertain significance ★★ ⚠ same condition
PEX3 p.Arg54Gln Uncertain significance ★★ ⚠ same condition
PEX3 p.Asn66Ser Uncertain significance ★★ ⚠ same condition
PEX3 p.Asp159Ala Uncertain significance ★★ ⚠ same condition
PEX3 p.Asp228Tyr Uncertain significance ★★ ⚠ same condition
PEX3 p.Asp305Glu Uncertain significance ★★ ⚠ same condition
PEX3 p.Glu44Lys Uncertain significance ★★ ⚠ same condition
PEX3 p.Gly252Arg 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/pex3-p-lys149arg (accessed [today's date]).

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