Is PAK3 p.Asn185Thr (c.554A>C) pathogenic?

PAK3 p.Asn185Thr (c.554A>C) is classified Uncertain significance in PAK3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-08-30). AlphaMissense: likely benign (0.0687); Ultra-rare (popmax 0.0141%, sas).

How common is PAK3 p.Asn185Thr (c.554A>C) in the general population?

PAK3 p.Asn185Thr (c.554A>C) is ultra-rare (popmax 0.0141%, sas) (gnomAD).

What do computational predictors say about PAK3 p.Asn185Thr (c.554A>C)?

AlphaMissense predicts likely benign (score 0.0687) — an in-silico prediction, not a clinical call.

PAK3 p.Asn185Thr

c.554A>C · rs751517340 · VCV426777

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0687 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0141%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0687	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -6.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.8	GERP 1.8, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 90 kb · p 0.00047 · regional, not allelic
Overall
CADD	22.1	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM N200T vs ClinVar N185T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0141% South Asian · 8/56,709 alleles

Filtering AF 0.00695% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00506%

Overall 0.000663% 8/1,206,059 alleles · ultra-rare

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: PAK3
Protein: p.Asn185Thr
Coding: c.554A>C
MANE Select: NM_001354046 · reported on NM_002578
dbSNP: rs751517340
Type: single nucleotide variant
Location: chrX:111163000 (GRCh38)
Structure: AlphaFold pLDDT 66.31 · 4 PDB
Residue 185: the sh3 domain

Full PAK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGEF7 p.Ser185Leu Uncertain significance ★ ⚠ same residue
PAK3 p.Asn185Ser Uncertain significance ★ ⚠ same residue
PAK3 p.Arg100Ter Pathogenic/Likely pathogenic ★★ same type
PAK3 p.Arg436Ter Pathogenic/Likely pathogenic ★★ same type
PAK3 p.Glu356Ter Pathogenic/Likely pathogenic ★★ same type
PAK3 c.830+6T>A Uncertain significance ★★ same type
PAK3 p.Ala490Thr Uncertain significance ★★ ⚠ same type
PAK3 p.Arg493Cys 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/pak3-p-asn185thr (accessed [today's date]).

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