Is NEB p.Pro3678= (c.11034G>A) pathogenic?

NEB p.Pro3678= (c.11034G>A) is classified Likely benign in NEB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-23). Very rare (popmax 0.00958%, nfe); Associated with nemaline myopathy 2.

What condition is associated with NEB p.Pro3678= (c.11034G>A)?

NEB p.Pro3678= (c.11034G>A) is associated with nemaline myopathy 2 (ClinVar).

How common is NEB p.Pro3678= (c.11034G>A) in the general population?

NEB p.Pro3678= (c.11034G>A) is very rare (popmax 0.00958%, 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.Pro3678=

c.11034G>A · rs528974814 · VCV703236

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00958%, nfe)

Conditions

nemaline myopathy 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -10	GERP -4.5
Overall
CADD	6.925	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00958% European (non-Finnish) · 113/1,179,858 alleles

Filtering AF 0.00809% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0076%

Overall 0.00737% 119/1,613,798 alleles · very rare exomes 108/1,461,656 · genomes 11/152,142 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00958%	10,441
Remaining individualsnot grpmax-eligible	0.0064%	15,614
Admixed American	0.00167%	59,998
South Asian	0.0011%	91,080

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.Pro3678=
Coding: c.11034G>A
MANE Select: NM_001164508
dbSNP: rs528974814
Type: single nucleotide variant
Location: chr2:151618317 (GRCh38)
Gene constraint: LOEUF 0.597 · pLI <0.01 (gnomAD)
Residue 3678: 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 p.Pro3678Ala Uncertain significance ★★ ⚠ same residue
NEB p.Pro3678Leu Conflicting classifications of pathogenicity ★ same residue
NEB p.Pro3678fs Pathogenic ★ same residue
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

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-pro3678 (accessed [today's date]).

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