Is PEX1 p.Asp512Val (c.1535A>T) pathogenic?

PEX1 p.Asp512Val (c.1535A>T) is classified Uncertain significance in PEX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-21). AlphaMissense: likely benign (0.0862); Very rare (popmax 0.00403%, afr); Associated with Zellweger spectrum disorders.

What condition is associated with PEX1 p.Asp512Val (c.1535A>T)?

PEX1 p.Asp512Val (c.1535A>T) is associated with Zellweger spectrum disorders (ClinVar).

How common is PEX1 p.Asp512Val (c.1535A>T) in the general population?

PEX1 p.Asp512Val (c.1535A>T) is very rare (popmax 0.00403%, afr) (gnomAD).

How is Zellweger syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PEX1 p.Asp512Val (c.1535A>T)?

AlphaMissense predicts likely benign (score 0.0862) — an in-silico prediction, not a clinical call.

PEX1 p.Asp512Val

c.1535A>T · rs1360273158 · VCV3023581

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0862 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00403%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Zellweger spectrum disorders

Computational evidence

Protein change
AlphaMissense	0.0862	likely benign
REVEL	0.459	indeterminate
SaProt	LLR -6.70	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.98 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 41 kb · p 4.3e-05 · regional, not allelic
Overall
CADD	17.98	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 0.00403% African / African-American · 3/74,406 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000497%

Overall 0.000252% 4/1,586,276 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00403%	24,802
Remaining individualsnot grpmax-eligible	0.00163%	61,522

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.Asp512Val
Coding: c.1535A>T
MANE Select: NM_000466
dbSNP: rs1360273158
Type: single nucleotide variant
Location: chr7:92510996 (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

Zellweger spectrum disorders — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Zellweger syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

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-asp512val (accessed [today's date]).

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