Is PAK4 p.Ala306Ser (c.916G>T) pathogenic?

PAK4 p.Ala306Ser (c.916G>T) is classified Uncertain significance in PAK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-25). AlphaMissense: likely benign (0.1799); Very rare (popmax 0.00401%, afr).

How common is PAK4 p.Ala306Ser (c.916G>T) in the general population?

PAK4 p.Ala306Ser (c.916G>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about PAK4 p.Ala306Ser (c.916G>T)?

AlphaMissense predicts likely benign (score 0.1799) — an in-silico prediction, not a clinical call.

PAK4 p.Ala306Ser

c.916G>T · VCV3413372

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1799 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1799	likely benign
REVEL	0.373	indeterminate
SaProt	LLR -9.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.49	acceptor gain · deltas
Pangolin	Δ0.36	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Overall
CADD	33.0	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 0.00401% African / African-American · 3/74,888 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,612,290 alleles · very rare exomes 0/1,460,168 · genomes 3/152,122 · 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.Ala306Ser
Coding: c.916G>T
MANE Select: NM_005884
Type: single nucleotide variant
Location: chr19:39173828 (GRCh38)
Gene constraint: LOEUF 1.268 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.26 · 50 PDB
Residue 306: the 'linker' region; an α-helix; the 'gef-interaction domain (gid)' 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-ala306ser (accessed [today's date]).

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