Is PEX1 p.Ala1237Val (c.3710C>T) pathogenic?

PEX1 p.Ala1237Val (c.3710C>T) is classified Uncertain significance in PEX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: ambiguous (0.4923); Very rare (popmax 0.00134%, afr); Associated with Zellweger spectrum disorders.

What condition is associated with PEX1 p.Ala1237Val (c.3710C>T)?

PEX1 p.Ala1237Val (c.3710C>T) is associated with Zellweger spectrum disorders (ClinVar).

How common is PEX1 p.Ala1237Val (c.3710C>T) in the general population?

PEX1 p.Ala1237Val (c.3710C>T) is very rare (popmax 0.00134%, 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.Ala1237Val (c.3710C>T)?

AlphaMissense predicts ambiguous (score 0.4923) — an in-silico prediction, not a clinical call.

PEX1 p.Ala1237Val

c.3710C>T · rs1473858573 · VCV1428334

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4923 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Zellweger spectrum disorders

Computational evidence

Protein change
AlphaMissense	0.4923	ambiguous
REVEL	0.749	pathogenic-leaning
SaProt	LLR -14.36	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP 4, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 41 kb · p 4.3e-05 · regional, not allelic
Overall
CADD	27.9	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 0.00134% African / African-American · 1/74,868 alleles

Overall 0.000186% 3/1,611,978 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,868
South Asian	0.0011%	91,010
European (non-Finnish)	8.49e-05%	1,178,318

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.Ala1237Val
Coding: c.3710C>T
MANE Select: NM_021167 · reported on NM_000466
dbSNP: rs1473858573
Type: single nucleotide variant
Location: chr7:92489350 (GRCh38)

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

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-ala1237val (accessed [today's date]).

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