Is PKN2 p.Asp976Ala (c.2927A>C) pathogenic?

PKN2 p.Asp976Ala (c.2927A>C) is classified Uncertain significance in PKN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-19). AlphaMissense: likely pathogenic (0.6412); Ultra-rare (popmax 0.0318%, sas).

How common is PKN2 p.Asp976Ala (c.2927A>C) in the general population?

PKN2 p.Asp976Ala (c.2927A>C) is ultra-rare (popmax 0.0318%, sas) (gnomAD).

What do computational predictors say about PKN2 p.Asp976Ala (c.2927A>C)?

AlphaMissense predicts likely pathogenic (score 0.6412) — an in-silico prediction, not a clinical call.

PKN2 p.Asp976Ala

c.2927A>C · VCV3889597

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6412 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0318%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6412	likely pathogenic
REVEL	0.65	pathogenic-leaning
SaProt	LLR -11.22	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 99 bp · p 0.055 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0318% South Asian · 29/91,066 alleles

Filtering AF 0.0228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0196%

Overall 0.0018% 29/1,613,160 alleles · ultra-rare exomes 28/1,461,104 · genomes 1/152,056 · 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: PKN2
Protein: p.Asp976Ala
Coding: c.2927A>C
MANE Select: NM_006256
Type: single nucleotide variant
Location: chr1:88833420 (GRCh38)
Gene constraint: LOEUF 0.428 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.06 · 4 PDB
Residue 976: the 'necessary for the catalytic activity' region; the agc-kinase c-terminal domain; a turn

Full PKN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PKN2 p.Ala30Thr Uncertain significance ★ ⚠ same type
PKN2 p.Ala355Pro Uncertain significance ★ ⚠ same type
PKN2 p.Ala923Thr Uncertain significance ★ ⚠ same type
PKN2 p.Arg130His Uncertain significance ★ ⚠ same type
PKN2 p.Arg130Leu Uncertain significance ★ ⚠ same type
PKN2 p.Arg20Gln Uncertain significance ★ ⚠ same type
PKN2 p.Arg223Lys Uncertain significance ★ ⚠ same type
PKN2 p.Arg223Ser 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/pkn2-p-asp976ala (accessed [today's date]).

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