Is PAK1 p.Ser133Pro (c.397T>C) pathogenic?

PAK1 p.Ser133Pro (c.397T>C) is classified Likely pathogenic in PAK1 (ClinVar, Single submitter, 2 submitters; last evaluated 2019-11-01). AlphaMissense: likely pathogenic (0.7348); Absent from gnomAD v4.1; Associated with intellectual developmental disorder with macrocephaly, seizures, and speech delay.

How common is PAK1 p.Ser133Pro (c.397T>C) in the general population?

PAK1 p.Ser133Pro (c.397T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PAK1 p.Ser133Pro (c.397T>C)?

AlphaMissense predicts likely pathogenic (score 0.7348) — an in-silico prediction, not a clinical call.

PAK1 p.Ser133Pro

Q: What condition is associated with PAK1 p.Ser133Pro (c.397T>C)?

PAK1 p.Ser133Pro (c.397T>C) is associated with intellectual developmental disorder with macrocephaly, seizures, and speech delay (ClinVar).

c.397T>C · rs2137081530 · VCV1325801

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7348 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intellectual developmental disorder with macrocephaly, seizures, and speech delay

Computational evidence

Protein change
AlphaMissense	0.7348	likely pathogenic ✓ concordant with ClinVar
REVEL	0.548	indeterminate
SaProt	LLR -13.67	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.30	constrained · MANE · 13 kb · p 1.2e-16 · regional, not allelic
Overall
CADD	26.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PAK1
Protein: p.Ser133Pro
Coding: c.397T>C
MANE Select: NM_002576
dbSNP: rs2137081530
Type: single nucleotide variant
Location: chr11:77379283 (GRCh38)
Gene constraint: LOEUF 0.705 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 73.90 · 41 PDB
Residue 133: the 'autoregulatory region' region; an α-helix

Full PAK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual developmental disorder with macrocephaly, seizures, and speech delay — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PAK1 p.Ser133Leu Uncertain significance ★ ⚠ same residue
PAK1 p.Ser133= Likely benign ★ same residue
PAK1 p.Ile476Thr Pathogenic/Likely pathogenic ★★ same condition
PAK1 p.Leu470Arg Likely pathogenic ★★ same condition
PAK1 p.Met143Thr Likely pathogenic ★★ same condition
PAK1 p.Pro121Leu Pathogenic ★★ same condition
PAK1 p.Pro121Ser Pathogenic/Likely pathogenic ★★ same condition
PAK1 p.Arg258Ter 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/pak1-p-ser133pro (accessed [today's date]).

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