Is PAK1 p.Pro168Ser (c.502C>T) pathogenic?

PAK1 p.Pro168Ser (c.502C>T) is classified Uncertain significance in PAK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-29). AlphaMissense: likely benign (0.0877); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PAK1 p.Pro168Ser (c.502C>T)?

PAK1 p.Pro168Ser (c.502C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PAK1 p.Pro168Ser (c.502C>T) in the general population?

PAK1 p.Pro168Ser (c.502C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about PAK1 p.Pro168Ser (c.502C>T)?

AlphaMissense predicts likely benign (score 0.0877) — an in-silico prediction, not a clinical call.

PAK1 p.Pro168Ser

c.502C>T · rs777870573 · VCV2531413

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0877 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0877	likely benign
REVEL	0.165	moderately benign-leaning
SaProt	LLR -6.35	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 9.9	GERP 1, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 30 kb · p 0.03 · regional, not allelic
Overall
CADD	24.2	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 0.000254% European (non-Finnish) · 3/1,179,398 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,056 alleles · very rare exomes 2/1,460,964 · genomes 1/152,092 · 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.Pro168Ser
Coding: c.502C>T
MANE Select: NM_002576
dbSNP: rs777870573
Type: single nucleotide variant
Location: chr11:77358993 (GRCh38)
Gene constraint: LOEUF 0.705 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 73.90 · 41 PDB
Residue 168: the 'disordered' region

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.Ala440Ser 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

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-pro168ser (accessed [today's date]).

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