Is PIM3 p.Arg181Pro (c.542G>C) pathogenic?

PIM3 p.Arg181Pro (c.542G>C) is classified Uncertain significance in PIM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-17). AlphaMissense: ambiguous (0.3617); Very rare (popmax 0.00224%, eas).

How common is PIM3 p.Arg181Pro (c.542G>C) in the general population?

PIM3 p.Arg181Pro (c.542G>C) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about PIM3 p.Arg181Pro (c.542G>C)?

AlphaMissense predicts ambiguous (score 0.3617) — an in-silico prediction, not a clinical call.

PIM3 p.Arg181Pro

c.542G>C · rs775149860 · VCV3213077

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3617 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3617	ambiguous
REVEL	0.195	benign-leaning
SaProt	LLR -9.76	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 8.2	GERP -0.91, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 2,176 bp · p 0.82 · regional, not allelic
Overall
CADD	25.4	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 0.00224% East Asian · 1/44,742 alleles

Overall 6.85e-05% 1/1,459,220 alleles · very 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: PIM3
Protein: p.Arg181Pro
Coding: c.542G>C
MANE Select: NM_001001852
dbSNP: rs775149860
Type: single nucleotide variant
Location: chr22:49961737 (GRCh38)
Gene constraint: LOEUF 1.002 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.64
Residue 181: the protein kinase domain

Full PIM3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PIM3 p.Asp32Glu Benign ★★ same type
PIM3 p.His222= Benign ★★ same type
PIM3 p.Pro313Ser Benign ★★ same type
PIM3 p.Val300Ala Benign ★★ same type
PIM3 p.Ala103Val Uncertain significance ★ ⚠ same type
PIM3 p.Ala31Gly Uncertain significance ★ ⚠ same type
PIM3 p.Ala31Val Uncertain significance ★ ⚠ same type
PIM3 p.Arg104Cys 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/pim3-p-arg181pro (accessed [today's date]).

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