Is PAK1 p.Ser220Pro (c.658T>C) pathogenic?

PAK1 p.Ser220Pro (c.658T>C) is classified Uncertain significance in PAK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-30). AlphaMissense: likely benign (0.1567); Very rare (popmax 8.48e-05%, nfe); Associated with intellectual developmental disorder with macrocephaly, seizures, and speech delay.

How common is PAK1 p.Ser220Pro (c.658T>C) in the general population?

PAK1 p.Ser220Pro (c.658T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about PAK1 p.Ser220Pro (c.658T>C)?

AlphaMissense predicts likely benign (score 0.1567) — an in-silico prediction, not a clinical call.

PAK1 p.Ser220Pro

Q: What condition is associated with PAK1 p.Ser220Pro (c.658T>C)?

PAK1 p.Ser220Pro (c.658T>C) is associated with intellectual developmental disorder with macrocephaly, seizures, and speech delay (ClinVar).

c.658T>C · rs1346690686 · VCV1333785

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1567 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intellectual developmental disorder with macrocephaly, seizures, and speech delay

Computational evidence

Protein change
AlphaMissense	0.1567	likely benign
REVEL	0.35	indeterminate
SaProt	LLR -6.42	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 30 kb · p 0.03 · regional, not allelic
Overall
CADD	21.4	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 8.48e-05% European (non-Finnish) · 1/1,179,404 alleles

Overall 6.84e-05% 1/1,461,134 alleles · very rare

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: PAK1
Protein: p.Ser220Pro
Coding: c.658T>C
MANE Select: NM_002576
dbSNP: rs1346690686
Type: single nucleotide variant
Location: chr11:77355782 (GRCh38)
Gene constraint: LOEUF 0.705 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 73.90 · 41 PDB
Residue 220: a modified residue (phosphoserine); the 'disordered' region

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.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
PAK1 p.Arg272Trp Uncertain significance ★★ ⚠ same condition
PAK1 p.Gly27Ser 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-ser220pro (accessed [today's date]).

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