Is PAK5 p.Ser415Arg (c.1245C>G) pathogenic?

PAK5 p.Ser415Arg (c.1245C>G) is classified Uncertain significance in PAK5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-19). AlphaMissense: likely pathogenic (0.8343); Very rare (popmax 8.48e-05%, nfe).

How common is PAK5 p.Ser415Arg (c.1245C>G) in the general population?

PAK5 p.Ser415Arg (c.1245C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about PAK5 p.Ser415Arg (c.1245C>G)?

AlphaMissense predicts likely pathogenic (score 0.8343) — an in-silico prediction, not a clinical call.

PAK5 p.Ser415Arg

c.1245C>G · VCV4130267

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8343 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8343	likely pathogenic
REVEL	0.086	moderately benign-leaning
SaProt	LLR -8.25	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 2.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	25.6	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 8.48e-05% European (non-Finnish) · 1/1,179,924 alleles

Overall 6.2e-05% 1/1,613,928 alleles · very rare exomes 1/1,461,722 · genomes 0/152,206 · 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: PAK5
Protein: p.Ser415Arg
Coding: c.1245C>G
MANE Select: NM_177990
Type: single nucleotide variant
Location: chr20:9566130 (GRCh38)
Gene constraint: LOEUF 0.329 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.09 · 2 PDB
Residue 415: 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-ser415arg (accessed [today's date]).

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