Is PAK4 p.Pro577Leu (c.1730C>T) pathogenic?

PAK4 p.Pro577Leu (c.1730C>T) is classified Uncertain significance in PAK4 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-04-10). AlphaMissense: likely benign (0.091); Very rare (popmax 0.0033%, sas).

How common is PAK4 p.Pro577Leu (c.1730C>T) in the general population?

PAK4 p.Pro577Leu (c.1730C>T) is very rare (popmax 0.0033%, sas) (gnomAD).

What do computational predictors say about PAK4 p.Pro577Leu (c.1730C>T)?

AlphaMissense predicts likely benign (score 0.091) — an in-silico prediction, not a clinical call.

PAK4 p.Pro577Leu

c.1730C>T · rs762977178 · VCV3064061

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.091 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.091	likely benign
REVEL	0.433	indeterminate
SaProt	LLR -10.40	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.8, phastCons 1
Overall
CADD	22.8	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 0.0033% South Asian · 3/90,954 alleles

Filtering AF 0.000876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000807% 13/1,610,746 alleles · very rare exomes 12/1,458,588 · genomes 1/152,158 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0033%	30,318
Remaining individualsnot grpmax-eligible	0.0016%	62,314
African / African-American	0.00134%	74,854
European (non-Finnish)	0.000679%	147,375

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.Pro577Leu
Coding: c.1730C>T
MANE Select: NM_005884
dbSNP: rs762977178
Type: single nucleotide variant
Location: chr19:39178533 (GRCh38)
Gene constraint: LOEUF 1.268 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.26 · 50 PDB
Residue 577: an α-helix

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-pro577leu (accessed [today's date]).

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