Is NPM1 p.Phe181= (c.543T>C) pathogenic?

NPM1 p.Phe181= (c.543T>C) is classified Benign/Likely benign in NPM1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-04-05). Low-frequency (popmax 3.28%, afr); Associated with acute myeloid leukemia.

What condition is associated with NPM1 p.Phe181= (c.543T>C)?

NPM1 p.Phe181= (c.543T>C) is associated with acute myeloid leukemia (ClinVar).

How common is NPM1 p.Phe181= (c.543T>C) in the general population?

NPM1 p.Phe181= (c.543T>C) is low-frequency (popmax 3.28%, afr) (gnomAD).

NPM1 p.Phe181=

c.543T>C · rs61755048 · VCV1336204

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.28%, afr)

Conditions

acute myeloid leukemia

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 1.6	GERP 1.3, phastCons 1
Overall
CADD	10.29	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.28% African / African-American · 2,451/74,674 alleles

Filtering AF 3.17% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.13%

Overall 0.168% 2,679/1,597,092 alleles · low-frequency exomes 1,302/1,444,792 · genomes 1,377/152,300 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.28%	30
Remaining individualsnot grpmax-eligible	0.168%	595
Admixed American	0.152%	659
Middle Eastern	0.0996%	1,004
South Asian	0.00661%	15,129
European (non-Finnish)	0.0018%	55,466

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.Phe181=
Coding: c.543T>C
MANE Select: NM_002520
dbSNP: rs61755048
Type: single nucleotide variant
Location: chr5:171400171 (GRCh38)
Gene constraint: LOEUF 0.313 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.42 · 8 PDB
Residue 181: the 'required for interaction with senp3' region; the 'disordered' region

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

Disease context

acute myeloid leukemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NPM1 c.847-5T>C Benign/Likely benign ★★ same condition
NPM1 p.Ter295= Pathogenic same condition
NPM1 c.*101T>C Uncertain significance same condition
NPM1 c.*29A>T Uncertain significance same condition
NPM1 c.*2A>G Uncertain significance same condition
NPM1 c.*33T>C Uncertain significance same condition
NPM1 c.*73T>C Uncertain significance same condition
NPM1 c.*75C>T Uncertain significance same condition

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-phe181 (accessed [today's date]).

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