Is NEB p.Pro1000Ser (c.2998C>T) pathogenic?

NEB p.Pro1000Ser (c.2998C>T) is classified Conflicting classifications of pathogenicity in NEB (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-04-11). AlphaMissense: ambiguous (0.5311); Very rare (popmax 0.00333%, amr); Associated with nemaline myopathy 2.

What condition is associated with NEB p.Pro1000Ser (c.2998C>T)?

NEB p.Pro1000Ser (c.2998C>T) is associated with nemaline myopathy 2 (ClinVar).

How common is NEB p.Pro1000Ser (c.2998C>T) in the general population?

NEB p.Pro1000Ser (c.2998C>T) is very rare (popmax 0.00333%, amr) (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.Pro1000Ser (c.2998C>T)?

AlphaMissense predicts ambiguous (score 0.5311) — an in-silico prediction, not a clinical call.

NEB p.Pro1000Ser

c.2998C>T · rs763910385 · VCV642351

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.5311 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

nemaline myopathy 2

Computational evidence

Protein change
AlphaMissense	0.5311	ambiguous
REVEL	0.332	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 82 kb · p 0.26 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,992 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00112% 18/1,613,186 alleles · very rare exomes 17/1,461,092 · genomes 1/152,094 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,996
European (non-Finnish)	0.00136%	73,713

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.Pro1000Ser
Coding: c.2998C>T
MANE Select: NM_001164508
dbSNP: rs763910385
Type: single nucleotide variant
Location: chr2:151680774 (GRCh38)
Gene constraint: LOEUF 0.597 · pLI <0.01 (gnomAD)
Residue 1000: 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.Pro1000Ala Uncertain significance ★ same residue
NEB p.Pro1000= 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

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-pro1000ser (accessed [today's date]).

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