Is NEB p.Ser8100= (c.24300G>C) pathogenic?

NEB p.Ser8100= (c.24300G>C) is classified Uncertain significance in NEB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-28). Ultra-rare (popmax 0.0166%, mid); Associated with nemaline myopathy 2.

What condition is associated with NEB p.Ser8100= (c.24300G>C)?

NEB p.Ser8100= (c.24300G>C) is associated with nemaline myopathy 2 (ClinVar).

How common is NEB p.Ser8100= (c.24300G>C) in the general population?

NEB p.Ser8100= (c.24300G>C) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

How is Severe congenital nemaline myopathy inherited?

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

NEB p.Ser8100=

c.24300G>C · rs541126160 · VCV510230

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Conditions

nemaline myopathy 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.605	indeterminate
Splicing
SpliceAI	Δ0.44	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.27	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1, phastCons 1
Overall
CADD	17.84	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,026 alleles

Filtering AF 0.00358% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00325%

Overall 0.00376% 59/1,569,106 alleles · ultra-rare exomes 52/1,417,238 · genomes 7/151,868 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,026
Remaining individualsnot grpmax-eligible	0.00493%	20,281
European (non-Finnish)	0.00459%	21,789
Ashkenazi Jewishnot grpmax-eligible	0.00345%	28,976
African / African-American	0.00135%	74,014

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.Ser8100=
Coding: c.24300G>C
MANE Select: NM_001164508
dbSNP: rs541126160
Type: single nucleotide variant
Location: chr2:151497626 (GRCh38)
Gene constraint: LOEUF 0.597 · pLI <0.01 (gnomAD)
Residue 8100: a UniProt-annotated variant site (in amc6)

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

For Severe congenital nemaline myopathy (Orphanet):

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

Similar variants

NEB c.11910+1G>A Likely pathogenic ★★★ same condition
NEB c.6076-1G>T Likely pathogenic ★★★ same condition
NEB c.78+1G>A Pathogenic ★★★ same condition
NEB p.Arg2313Ter Pathogenic ★★★ same condition
NEB p.Asp498Gly Likely pathogenic ★★★ ⚠ same condition
NEB p.Ser6366Ile Pathogenic ★★★ same condition
NEB p.Ser6648= Pathogenic ★★★ same condition
NEB c.22590+2T>C 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/neb-p-ser8100 (accessed [today's date]).

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