Is NPM1 p.Pro14= (c.42C>T) pathogenic?

NPM1 p.Pro14= (c.42C>T) is classified Likely benign in NPM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-01). Very rare (popmax 0.0011%, sas).

How common is NPM1 p.Pro14= (c.42C>T) in the general population?

NPM1 p.Pro14= (c.42C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

NPM1 p.Pro14=

c.42C>T · VCV3905545

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.91	GERP -5.5, phastCons 0.004
Overall
CADD	10.58	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,024 alleles

Overall 6.85e-05% 1/1,460,754 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: NPM1
Protein: p.Pro14=
Coding: c.42C>T
MANE Select: NM_002520
Type: single nucleotide variant
Location: chr5:171387990 (GRCh38)
Gene constraint: LOEUF 0.313 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.42 · 8 PDB
Residue 14: the 'required for interaction with senp3' region; the 'necessary for interaction with apex1' region

Full NPM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NPM1 c.847-5T>C Benign/Likely benign ★★ same type
NPM1 p.Asp165= Benign/Likely benign ★★ same type
NPM1 p.Phe181= Benign/Likely benign ★★ same type
NPM1 p.Ala201Asp Uncertain significance ★ ⚠ same type
NPM1 p.Asp171Glu Uncertain significance ★ ⚠ same type
NPM1 p.Asp178Val Uncertain significance ★ ⚠ same type
NPM1 p.Ile196Thr Uncertain significance ★ ⚠ same type
NPM1 p.Ile269Val 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/npm1-p-pro14 (accessed [today's date]).

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