Is PAK4 p.Arg159Ser (c.477G>T) pathogenic?

PAK4 p.Arg159Ser (c.477G>T) is classified Uncertain significance in PAK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-30). AlphaMissense: ambiguous (0.5369); Very rare (popmax 0.00969%, eas).

How common is PAK4 p.Arg159Ser (c.477G>T) in the general population?

PAK4 p.Arg159Ser (c.477G>T) is very rare (popmax 0.00969%, eas) (gnomAD).

What do computational predictors say about PAK4 p.Arg159Ser (c.477G>T)?

AlphaMissense predicts ambiguous (score 0.5369) — an in-silico prediction, not a clinical call.

PAK4 p.Arg159Ser

c.477G>T · rs1172447216 · VCV2247374

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5369 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00969%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5369	ambiguous
REVEL	0.283	benign-leaning
SaProt	LLR -6.78	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 0.96, phastCons 1
Overall
CADD	21.0	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 0.00969% East Asian · 4/41,268 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00192%

Overall 0.000453% 7/1,545,594 alleles · very rare exomes 7/1,393,348 · genomes 0/152,246 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00969%	10,317
European (non-Finnish)	0.000262%	381,095

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.Arg159Ser
Coding: c.477G>T
MANE Select: NM_005884
dbSNP: rs1172447216
Type: single nucleotide variant
Location: chr19:39173190 (GRCh38)
Gene constraint: LOEUF 1.268 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.26 · 50 PDB
Residue 159: the 'linker' region; the 'disordered' region

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

Similar variants

PAK4 p.Arg159Thr Uncertain significance ★ ⚠ same residue
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

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-arg159ser (accessed [today's date]).

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