Is NEB p.Phe993= (c.2979T>C) pathogenic?

NEB p.Phe993= (c.2979T>C) is classified Likely benign in NEB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-24). Rare (popmax 0.111%, eas); Associated with nemaline myopathy 2.

What condition is associated with NEB p.Phe993= (c.2979T>C)?

NEB p.Phe993= (c.2979T>C) is associated with nemaline myopathy 2 (ClinVar).

How common is NEB p.Phe993= (c.2979T>C) in the general population?

NEB p.Phe993= (c.2979T>C) is rare (popmax 0.111%, eas) (gnomAD).

How is Severe congenital nemaline myopathy inherited?

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

NEB p.Phe993=

c.2979T>C · rs780408206 · VCV725912

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.111%, eas)

Conditions

nemaline myopathy 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP -1.8, phastCons 1
Overall
CADD	8.19	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.111% East Asian · 50/44,846 alleles

Filtering AF 0.0868% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0781%

Overall 0.00341% 55/1,613,360 alleles · rare exomes 52/1,461,172 · genomes 3/152,188 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.111%	897
Middle Eastern	0.0165%	6,078
Remaining individualsnot grpmax-eligible	0.0048%	20,817
European (non-Finnish)	8.48e-05%	1,179,504

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.Phe993=
Coding: c.2979T>C
MANE Select: NM_001164508
dbSNP: rs780408206
Type: single nucleotide variant
Location: chr2:151680793 (GRCh38)
Gene constraint: LOEUF 0.597 · pLI <0.01 (gnomAD)
Residue 993: 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 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-phe993 (accessed [today's date]).

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