Is NEB p.Val2004Ala (c.6011T>C) pathogenic?

NEB p.Val2004Ala (c.6011T>C) is classified Conflicting classifications of pathogenicity in NEB (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-09). AlphaMissense: ambiguous (0.4115); Very rare (popmax 0.00526%, nfe); Associated with nemaline myopathy 2.

What condition is associated with NEB p.Val2004Ala (c.6011T>C)?

NEB p.Val2004Ala (c.6011T>C) is associated with nemaline myopathy 2 (ClinVar).

How common is NEB p.Val2004Ala (c.6011T>C) in the general population?

NEB p.Val2004Ala (c.6011T>C) is very rare (popmax 0.00526%, 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.Val2004Ala (c.6011T>C)?

AlphaMissense predicts ambiguous (score 0.4115) — an in-silico prediction, not a clinical call.

NEB p.Val2004Ala

c.6011T>C · rs764064217 · VCV1018771

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4115 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00526%, nfe)

Conditions

nemaline myopathy 2

Computational evidence

Protein change
AlphaMissense	0.4115	ambiguous
REVEL	0.15	moderately benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 82 kb · p 0.26 · regional, not allelic
Overall
CADD	23.7	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 0.00526% European (non-Finnish) · 62/1,179,308 alleles

Filtering AF 0.00419% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.00403% 65/1,613,042 alleles · very rare exomes 59/1,460,918 · genomes 6/152,124 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00526%	19,021
African / African-American	0.00267%	37,426
Remaining individualsnot grpmax-eligible	0.0016%	62,414

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.Val2004Ala
Coding: c.6011T>C
MANE Select: NM_001164508
dbSNP: rs764064217
Type: single nucleotide variant
Location: chr2:151659129 (GRCh38)
Gene constraint: LOEUF 0.597 · pLI <0.01 (gnomAD)
Residue 2004: 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

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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-val2004ala (accessed [today's date]).

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