Is PAK4 p.Ser244Phe (c.731C>T) pathogenic?

PAK4 p.Ser244Phe (c.731C>T) is classified Uncertain significance in PAK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-10). AlphaMissense: likely benign (0.1054); Ultra-rare (popmax 0.0153%, sas).

How common is PAK4 p.Ser244Phe (c.731C>T) in the general population?

PAK4 p.Ser244Phe (c.731C>T) is ultra-rare (popmax 0.0153%, sas) (gnomAD).

What do computational predictors say about PAK4 p.Ser244Phe (c.731C>T)?

AlphaMissense predicts likely benign (score 0.1054) — an in-silico prediction, not a clinical call.

PAK4 p.Ser244Phe

c.731C>T · rs771728038 · VCV3208047

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1054 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0153%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1054	likely benign
REVEL	0.119	moderately benign-leaning
SaProt	LLR -9.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.7	GERP 1.1, phastCons 0.77
Overall
CADD	18.61	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 0.0153% South Asian · 13/84,754 alleles

Filtering AF 0.00903% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00717%

Overall 0.000827% 13/1,571,598 alleles · ultra-rare exomes 13/1,419,436 · genomes 0/152,162 · 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: PAK4
Protein: p.Ser244Phe
Coding: c.731C>T
MANE Select: NM_005884
dbSNP: rs771728038
Type: single nucleotide variant
Location: chr19:39173643 (GRCh38)
Gene constraint: LOEUF 1.268 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.26 · 50 PDB
Residue 244: the 'linker' region; the 'disordered' 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-ser244phe (accessed [today's date]).

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