Is PAK1 p.Arg371Cys (c.1111C>T) pathogenic?

PAK1 p.Arg371Cys (c.1111C>T) is classified Likely pathogenic in PAK1 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.8522); Very rare (popmax 0.000176%, nfe); Associated with intellectual developmental disorder with macrocephaly, seizures, and speech delay.

How common is PAK1 p.Arg371Cys (c.1111C>T) in the general population?

PAK1 p.Arg371Cys (c.1111C>T) is very rare (popmax 0.000176%, nfe) (gnomAD).

What do computational predictors say about PAK1 p.Arg371Cys (c.1111C>T)?

AlphaMissense predicts likely pathogenic (score 0.8522) — an in-silico prediction, not a clinical call.

PAK1 p.Arg371Cys

Q: What condition is associated with PAK1 p.Arg371Cys (c.1111C>T)?

PAK1 p.Arg371Cys (c.1111C>T) is associated with intellectual developmental disorder with macrocephaly, seizures, and speech delay (ClinVar).

c.1111C>T · rs1483962098 · VCV2506575

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8522 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000176%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

intellectual developmental disorder with macrocephaly, seizures, and speech delay

Computational evidence

Protein change
AlphaMissense	0.8522	likely pathogenic ✓ concordant with ClinVar
REVEL	0.628	indeterminate
SaProt	LLR -14.34	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 0.99, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 3,337 bp · p 0.0011 · regional, not allelic
Overall
CADD	34.0	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 0.000176% European (non-Finnish) · 2/1,133,830 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000128% 2/1,563,604 alleles · very rare exomes 2/1,411,324 · genomes 0/152,280 · 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: PAK1
Protein: p.Arg371Cys
Coding: c.1111C>T
MANE Select: NM_002576
dbSNP: rs1483962098
Type: single nucleotide variant
Location: chr11:77340651 (GRCh38)
Gene constraint: LOEUF 0.705 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 73.90 · 41 PDB
Residue 371: the protein kinase domain; 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.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-arg371cys (accessed [today's date]).

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