Is PAK4 p.Leu53= (c.159C>T) pathogenic?

PAK4 p.Leu53= (c.159C>T) is classified Likely benign in PAK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-01). Ultra-rare (popmax 0.012%, afr).

How common is PAK4 p.Leu53= (c.159C>T) in the general population?

PAK4 p.Leu53= (c.159C>T) is ultra-rare (popmax 0.012%, afr) (gnomAD).

PAK4 p.Leu53=

c.159C>T · VCV4822232

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

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 -4.7	GERP -5.5
Overall
CADD	0.793	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% African / African-American · 9/74,882 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00292% 47/1,610,850 alleles · ultra-rare exomes 38/1,458,720 · genomes 9/152,130 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,320
East Asian	0.00446%	22,426
European (non-Finnish)	0.00297%	33,684
Admixed American	0.00167%	59,916

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: PAK4
Protein: p.Leu53=
Coding: c.159C>T
MANE Select: NM_005884
Type: single nucleotide variant
Location: chr19:39169712 (GRCh38)
Gene constraint: LOEUF 1.268 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.26 · 50 PDB
Residue 53: the 'linker' region

Full PAK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PAK4 p.Ala573Ser Benign ★★ same type
PAK4 p.Ala109Asp Uncertain significance ★ ⚠ same type
PAK4 p.Ala111Ser Uncertain significance ★ ⚠ same type
PAK4 p.Ala125Asp Uncertain significance ★ ⚠ same type
PAK4 p.Ala13Ser Uncertain significance ★ ⚠ same type
PAK4 p.Ala13Thr Uncertain significance ★ ⚠ same type
PAK4 p.Ala13Val Uncertain significance ★ ⚠ same type
PAK4 p.Ala154Ser 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/pak4-p-leu53 (accessed [today's date]).

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