Is PAK5 p.Pro187Ser (c.559C>T) pathogenic?

PAK5 p.Pro187Ser (c.559C>T) is classified Uncertain significance in PAK5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-20). AlphaMissense: likely benign (0.0789); Very rare (popmax 0.00133%, afr).

How common is PAK5 p.Pro187Ser (c.559C>T) in the general population?

PAK5 p.Pro187Ser (c.559C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PAK5 p.Pro187Ser (c.559C>T)?

AlphaMissense predicts likely benign (score 0.0789) — an in-silico prediction, not a clinical call.

PAK5 p.Pro187Ser

c.559C>T · VCV3303974

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0789 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0789	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -6.62	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 3.1	GERP -1.2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	14.71	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 0.00133% African / African-American · 1/74,996 alleles

Overall 0.000124% 2/1,614,032 alleles · very rare exomes 2/1,461,882 · genomes 0/152,150 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,996
South Asian	0.0011%	91,072

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.Pro187Ser
Coding: c.559C>T
MANE Select: NM_177990
Type: single nucleotide variant
Location: chr20:9580576 (GRCh38)
Gene constraint: LOEUF 0.329 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.09 · 2 PDB
Residue 187: a UniProt-annotated variant site (in); the 'linker' region

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

Similar variants

PAK5 p.Leu490= Benign ★★ same type
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

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-pro187ser (accessed [today's date]).

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