Is NEB p.Pro2741Ser (c.8221C>T) pathogenic?

NEB p.Pro2741Ser (c.8221C>T) is classified Uncertain significance in NEB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-16). AlphaMissense: ambiguous (0.4487); Very rare (popmax 0.00334%, amr); Associated with NEB-related disorder.

What condition is associated with NEB p.Pro2741Ser (c.8221C>T)?

NEB p.Pro2741Ser (c.8221C>T) is associated with NEB-related disorder, nemaline myopathy 2 (ClinVar).

How common is NEB p.Pro2741Ser (c.8221C>T) in the general population?

NEB p.Pro2741Ser (c.8221C>T) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about NEB p.Pro2741Ser (c.8221C>T)?

AlphaMissense predicts ambiguous (score 0.4487) — an in-silico prediction, not a clinical call.

NEB p.Pro2741Ser

c.8221C>T · rs1259955139 · VCV2159575

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4487 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Conditions

NEB-related disorder

Computational evidence

Protein change
AlphaMissense	0.4487	ambiguous
REVEL	0.536	indeterminate
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 0.90	unconstrained · MANE · 37 kb · p 2.1e-05 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00334% Admixed American · 2/59,932 alleles

Filtering AF 0.000554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000205% 3/1,460,742 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,966
European (non-Finnish)	8.48e-05%	1,179,357

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.Pro2741Ser
Coding: c.8221C>T
MANE Select: NM_001164508
dbSNP: rs1259955139
Type: single nucleotide variant
Location: chr2:151642809 (GRCh38)
Gene constraint: LOEUF 0.597 · pLI <0.01 (gnomAD)
Residue 2741: a UniProt-annotated variant site (in amc6)

Full NEB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

NEB-related disorder

Also linked: nemaline myopathy 2

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-pro2741ser (accessed [today's date]).

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