Is NEB p.Pro509fs (c.1526del) pathogenic?

NEB p.Pro509fs (c.1526del) is classified Pathogenic/Likely pathogenic in NEB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-11). Very rare (popmax 0.000339%, nfe); Associated with nemaline myopathy 2.

What condition is associated with NEB p.Pro509fs (c.1526del)?

NEB p.Pro509fs (c.1526del) is associated with nemaline myopathy 2, arthrogryposis multiplex congenita 6 (ClinVar).

How common is NEB p.Pro509fs (c.1526del) in the general population?

NEB p.Pro509fs (c.1526del) is very rare (popmax 0.000339%, nfe) (gnomAD).

How is Severe congenital nemaline myopathy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

NEB p.Pro509fs

c.1526del · rs1181351466 · VCV1452031

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

nemaline myopathy 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 17 of 182
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.17	GERP -3, phastCons 0.001
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,816 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,768 alleles · very rare exomes 2/1,461,578 · genomes 2/152,190 · 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: NEB
Protein: p.Pro509fs
Coding: c.1526del
MANE Select: NM_001164508
dbSNP: rs1181351466
Type: Deletion
Location: chr2:151696680 (GRCh38)
Gene constraint: LOEUF 0.597 · pLI <0.01 (gnomAD)

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

Disease context

nemaline myopathy 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: arthrogryposis multiplex congenita 6

For Severe congenital nemaline myopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

NEB p.Pro509Ser Likely benign ★ ⚠ same residue
NEB p.Ala339fs Uncertain significance ★★★ same condition
NEB c.1570-2del Pathogenic/Likely pathogenic ★★ same condition
NEB c.22272+2_22272+3del Likely pathogenic ★★ same condition
NEB c.3252_3255+3del Pathogenic/Likely pathogenic ★★ same condition
NEB c.403-6_405del Likely pathogenic ★★ same condition
NEB c.5032-1del Likely pathogenic ★★ same condition
NEB p.Ala1542fs Pathogenic/Likely pathogenic ★★ 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/neb-p-pro509fs (accessed [today's date]).

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