Is PAK1 p.Ala440Ser (c.1318G>T) pathogenic?

PAK1 p.Ala440Ser (c.1318G>T) is classified Uncertain significance in PAK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely benign (0.259); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PAK1 p.Ala440Ser (c.1318G>T)?

PAK1 p.Ala440Ser (c.1318G>T) is associated with Inborn genetic diseases (ClinVar).

How common is PAK1 p.Ala440Ser (c.1318G>T) in the general population?

PAK1 p.Ala440Ser (c.1318G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PAK1 p.Ala440Ser (c.1318G>T)?

AlphaMissense predicts likely benign (score 0.259) — an in-silico prediction, not a clinical call.

PAK1 p.Ala440Ser

c.1318G>T · VCV4130216

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.259 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.259	likely benign
REVEL	0.294	indeterminate
SaProt	LLR -11.12	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 13 kb · p 1.6e-12 · regional, not allelic
Overall
CADD	28.6	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.Ala440Ser
Coding: c.1318G>T
MANE Select: NM_002576
Type: single nucleotide variant
Location: chr11:77336181 (GRCh38)
Gene constraint: LOEUF 0.705 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 73.90 · 41 PDB
Residue 440: the protein kinase domain

Full PAK1 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

PAK1 p.Ala524Pro Uncertain significance ★★ ⚠ same condition
PAK1 c.1117-3T>C Uncertain significance ★ same condition
PAK1 p.Arg203Trp Uncertain significance ★ ⚠ same condition
PAK1 p.Arg237Trp Uncertain significance ★ ⚠ same condition
PAK1 p.Arg421Trp Conflicting classifications of pathogenicity ★ ⚠ same condition
PAK1 p.Arg471Lys Uncertain significance ★ ⚠ same condition
PAK1 p.Arg56Gln Uncertain significance ★ ⚠ same condition
PAK1 p.Asn227Lys 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-ala440ser (accessed [today's date]).

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