Is NEB p.Ser45fs (c.133_146del) pathogenic?

NEB p.Ser45fs (c.133146del) is classified Pathogenic/Likely pathogenic in NEB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-01). Very rare (popmax 0.00446%, eas); Associated with arthrogryposis multiplex congenita 6.

What condition is associated with NEB p.Ser45fs (c.133_146del)?

NEB p.Ser45fs (c.133_146del) is associated with arthrogryposis multiplex congenita 6, nemaline myopathy 2, nemaline myopathy (ClinVar).

How common is NEB p.Ser45fs (c.133_146del) in the general population?

NEB p.Ser45fs (c.133_146del) is very rare (popmax 0.00446%, eas) (gnomAD).

NEB p.Ser45fs

c.133_146del · rs1321522421 · VCV1072759

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

arthrogryposis multiplex congenita 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 182
Splicing
SpliceAI	—	not assessed · substitutions only
Overall
CADD	31.0	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 0.00446% East Asian · 2/44,840 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000124% 2/1,611,220 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: NEB
Protein: p.Ser45fs
Coding: c.133_146del
MANE Select: NM_001164508
dbSNP: rs1321522421
Type: Deletion
Location: chr2:151727839 (GRCh38)
Gene constraint: LOEUF 0.597 · pLI <0.01 (gnomAD)
Residue 45: the 'disordered' region

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

Disease context

arthrogryposis multiplex congenita 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nemaline myopathy 2 nemaline myopathy

Similar variants

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
NEB p.Ala247fs 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-ser45fs (accessed [today's date]).

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