Is PAK5 p.Leu490= (c.1468C>T) pathogenic?

PAK5 p.Leu490= (c.1468C>T) is classified Benign in PAK5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-12). Common (popmax 27.7%, eas) — too common for a highly-penetrant pathogenic allele.

PAK5 p.Leu490=

Q: How common is PAK5 p.Leu490= (c.1468C>T) in the general population?

PAK5 p.Leu490= (c.1468C>T) is common (popmax 27.7%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1468C>T · rs6133723 · VCV1676927

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 27.7%, eas) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 0.46, phastCons 1
Overall
CADD	6.377	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 27.7% East Asian · 12,426/44,822 alleles

Filtering AF 27.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 27.1%

Overall 5.59% 90,200/1,612,356 alleles · common exomes 82,253/1,460,288 · genomes 7,947/152,068 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	27.7%	4
Finnishnot grpmax-eligible	6.45%	15
Remaining individualsnot grpmax-eligible	5.95%	17
Ashkenazi Jewishnot grpmax-eligible	5.85%	17
South Asian	5.22%	19
European (non-Finnish)	5.11%	20
Amishnot grpmax-eligible	4.08%	24
African / African-American	2.52%	40
Admixed American	2.02%	49
Middle Eastern	1.62%	62

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: PAK5
Protein: p.Leu490=
Coding: c.1468C>T
MANE Select: NM_177990
dbSNP: rs6133723
Type: single nucleotide variant
Location: chr20:9565907 (GRCh38)
Gene constraint: LOEUF 0.329 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.09 · 2 PDB
Residue 490: the protein kinase domain; an α-helix

Full PAK5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PAK5 p.Leu603= Benign ★★ same type
PAK5 p.Lys216= Benign ★★ same type
PAK5 p.Tyr333= Benign ★★ same type
PAK5 p.Ala120Gly Uncertain significance ★ ⚠ same type
PAK5 p.Ala120Val Uncertain significance ★ ⚠ same type
PAK5 p.Ala251Val Uncertain significance ★ ⚠ same type
PAK5 p.Ala303Thr Uncertain significance ★ ⚠ same type
PAK5 p.Ala380Gly Uncertain significance ★ ⚠ same type

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/pak5-p-leu490 (accessed [today's date]).

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