Is NES p.Glu8Val (c.23A>T) pathogenic?

NES p.Glu8Val (c.23A>T) is classified Uncertain significance in NES (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-27). AlphaMissense: likely pathogenic (0.8814); Very rare (popmax 0.00102%, nfe); Associated with congenital fibrosis of extraocular muscles.

What condition is associated with NES p.Glu8Val (c.23A>T)?

NES p.Glu8Val (c.23A>T) is associated with congenital fibrosis of extraocular muscles (ClinVar).

How common is NES p.Glu8Val (c.23A>T) in the general population?

NES p.Glu8Val (c.23A>T) is very rare (popmax 0.00102%, nfe) (gnomAD).

How is Congenital fibrosis of extraocular muscles inherited?

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

What do computational predictors say about NES p.Glu8Val (c.23A>T)?

AlphaMissense predicts likely pathogenic (score 0.8814) — an in-silico prediction, not a clinical call.

NES p.Glu8Val

c.23A>T · rs566053868 · VCV2301221

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8814 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital fibrosis of extraocular muscles

Computational evidence

Protein change
AlphaMissense	0.8814	likely pathogenic · top 2% in NES
REVEL	0.92	moderately pathogenic-leaning
SaProt	LLR -9.56	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.29	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 7,939 bp · p 0.0089 · regional, not allelic
Overall
CADD	29.2	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 0.00102% European (non-Finnish) · 12/1,179,780 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000744% 12/1,612,116 alleles · very rare exomes 9/1,460,116 · genomes 3/152,000 · joint denominator

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: NES
Protein: p.Glu8Val
Coding: c.23A>T
MANE Select: NM_006617
dbSNP: rs566053868
Type: single nucleotide variant
Location: chr1:156677242 (GRCh38)
Gene constraint: LOEUF 1.264 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.18
Residue 8: the if rod domain; the 'coil 1a' region

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

Disease context

congenital fibrosis of extraocular muscles — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital fibrosis of extraocular muscles (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

NES p.Glu8= Likely benign ★ same residue
NES p.Arg342Gln Benign ★★ same type
NES p.Glu609Gln Benign ★★ same type
NES p.Gly1407Arg Benign ★★ same type
NES p.Leu412= Benign ★★ same type
NES p.Lys830Arg Benign ★★ same type
NES p.Pro1275Leu Benign ★★ same type
NES p.Ser1466Gly Benign ★★ same type

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/nes-p-glu8val (accessed [today's date]).

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