Is NEB p.Pro6283Ser (c.18847C>T) pathogenic?

NEB p.Pro6283Ser (c.18847C>T) is classified Uncertain significance in NEB (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-23). AlphaMissense: likely benign (0.1414); Very rare (popmax 0.00134%, afr); Associated with nemaline myopathy 2.

What condition is associated with NEB p.Pro6283Ser (c.18847C>T)?

NEB p.Pro6283Ser (c.18847C>T) is associated with nemaline myopathy 2 (ClinVar).

How common is NEB p.Pro6283Ser (c.18847C>T) in the general population?

NEB p.Pro6283Ser (c.18847C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

How is Severe congenital nemaline myopathy inherited?

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

What do computational predictors say about NEB p.Pro6283Ser (c.18847C>T)?

AlphaMissense predicts likely benign (score 0.1414) — an in-silico prediction, not a clinical call.

NEB p.Pro6283Ser

c.18847C>T · rs2096144047 · VCV1920644

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1414 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

nemaline myopathy 2

Computational evidence

Protein change
AlphaMissense	0.1414	likely benign
REVEL	0.292	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 91 kb · p 4.4e-06 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P4582S vs ClinVar P6283S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,644 alleles

Overall 6.27e-05% 1/1,595,392 alleles · very rare exomes 0/1,443,266 · genomes 1/152,126 · 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.Pro6283Ser
Coding: c.18847C>T
MANE Select: NM_001164508
dbSNP: rs2096144047
Type: single nucleotide variant
Location: chr2:151562655 (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

For Severe congenital nemaline myopathy (Orphanet):

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

Similar variants

NEB p.Pro6283= Likely benign ★ 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
NEB p.Ser6366Ile Pathogenic ★★★ same condition
NEB p.Ser6648= 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-pro6283ser (accessed [today's date]).

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