Is PEX1 p.Ser649Ala (c.1945T>G) pathogenic?

PEX1 p.Ser649Ala (c.1945T>G) is classified Uncertain significance in PEX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely benign (0.0668); Very rare (popmax 0.00212%, nfe); Associated with peroxisome biogenesis disorder 1A (Zellweger).

What condition is associated with PEX1 p.Ser649Ala (c.1945T>G)?

PEX1 p.Ser649Ala (c.1945T>G) is associated with peroxisome biogenesis disorder 1A (Zellweger) (ClinVar).

How common is PEX1 p.Ser649Ala (c.1945T>G) in the general population?

PEX1 p.Ser649Ala (c.1945T>G) is very rare (popmax 0.00212%, nfe) (gnomAD).

What do computational predictors say about PEX1 p.Ser649Ala (c.1945T>G)?

AlphaMissense predicts likely benign (score 0.0668) — an in-silico prediction, not a clinical call.

PEX1 p.Ser649Ala

c.1945T>G · rs1251466114 · VCV909480

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0668 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

peroxisome biogenesis disorder 1A (Zellweger)

Computational evidence

Protein change
AlphaMissense	0.0668	likely benign
REVEL	0.247	benign-leaning
SaProt	LLR -6.02	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 1.1	GERP 0.24, phastCons 0.99
Regional constraint	o/e 0.89	unconstrained · MANE · 41 kb · p 4.3e-05 · regional, not allelic
Overall
CADD	14.22	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 0.00212% European (non-Finnish) · 25/1,179,918 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00155% 25/1,613,964 alleles · very rare exomes 24/1,461,740 · genomes 1/152,224 · joint denominator

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.Ser649Ala
Coding: c.1945T>G
MANE Select: NM_000466
dbSNP: rs1251466114
Type: single nucleotide variant
Location: chr7:92504858 (GRCh38)
Gene constraint: LOEUF 0.746 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.19
Residue 649: a UniProt-annotated variant site (in pbd1a and pbd1b)

Full PEX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

peroxisome biogenesis disorder 1A (Zellweger) — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PEX1 p.Ser649Leu Uncertain significance ★ ⚠ same residue
PEX1 p.Ser649= Likely benign ★ same residue
PEX1 c.1239+1G>T Pathogenic ★★ same condition
PEX1 c.130-1G>T 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

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-ser649ala (accessed [today's date]).

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