Is NES p.Arg766Trp (c.2296C>T) pathogenic?

NES p.Arg766Trp (c.2296C>T) is classified Uncertain significance in NES (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-11). AlphaMissense: likely benign (0.0867); Very rare (popmax 0.00223%, eas).

How common is NES p.Arg766Trp (c.2296C>T) in the general population?

NES p.Arg766Trp (c.2296C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about NES p.Arg766Trp (c.2296C>T)?

AlphaMissense predicts likely benign (score 0.0867) — an in-silico prediction, not a clinical call.

NES p.Arg766Trp

c.2296C>T · rs767060003 · VCV2514961

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0867 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0867	likely benign
REVEL	0.313	indeterminate
SaProt	LLR -6.98	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.83	GERP -2.5
Regional constraint	o/e 0.94	unconstrained · MANE · 7,939 bp · p 0.0089 · regional, not allelic
Overall
CADD	9.514	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,876 alleles

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

Overall 0.000929% 15/1,613,866 alleles · very rare exomes 12/1,461,752 · genomes 3/152,114 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,876
Remaining individualsnot grpmax-eligible	0.0016%	62,482
African / African-American	0.00134%	74,888
European (non-Finnish)	0.00102%	98,329

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.Arg766Trp
Coding: c.2296C>T
MANE Select: NM_006617
dbSNP: rs767060003
Type: single nucleotide variant
Location: chr1:156671892 (GRCh38)
Gene constraint: LOEUF 1.264 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.18
Residue 766: the 'tail' region; the 'disordered' region

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

Similar variants

NES p.Glu8Val Uncertain significance ★★ ⚠ same type
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-arg766trp (accessed [today's date]).

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