Is NEB p.Pro2011Ser (c.6031C>T) pathogenic?

NEB p.Pro2011Ser (c.6031C>T) is classified Uncertain significance in NEB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-30). AlphaMissense: likely pathogenic (0.6066); Very rare (popmax 8.48e-05%, nfe); Associated with nemaline myopathy 2.

What condition is associated with NEB p.Pro2011Ser (c.6031C>T)?

NEB p.Pro2011Ser (c.6031C>T) is associated with nemaline myopathy 2 (ClinVar).

How common is NEB p.Pro2011Ser (c.6031C>T) in the general population?

NEB p.Pro2011Ser (c.6031C>T) is very rare (popmax 8.48e-05%, nfe) (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.Pro2011Ser (c.6031C>T)?

AlphaMissense predicts likely pathogenic (score 0.6066) — an in-silico prediction, not a clinical call.

NEB p.Pro2011Ser

c.6031C>T · rs1474856568 · VCV1968623

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6066 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

nemaline myopathy 2

Computational evidence

Protein change
AlphaMissense	0.6066	likely pathogenic
REVEL	0.646	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 82 kb · p 0.26 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,124 alleles

Overall 0.000205% 3/1,460,754 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,219
European (non-Finnish)grpmax	8.48e-05%	1,179,124

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro2011Ser
Coding: c.6031C>T
MANE Select: NM_001164508
dbSNP: rs1474856568
Type: single nucleotide variant
Location: chr2:151659109 (GRCh38)
Gene constraint: LOEUF 0.597 · pLI <0.01 (gnomAD)
Residue 2011: 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.Pro2011= Conflicting classifications of pathogenicity ★ same residue
NEB p.Pro2011Leu Uncertain significance ★ 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-pro2011ser (accessed [today's date]).

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