Is NES p.Arg285Trp (c.853C>T) pathogenic?

NES p.Arg285Trp (c.853C>T) is classified Uncertain significance in NES (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-02). AlphaMissense: ambiguous (0.4179); Very rare (popmax 0.005%, amr).

How common is NES p.Arg285Trp (c.853C>T) in the general population?

NES p.Arg285Trp (c.853C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about NES p.Arg285Trp (c.853C>T)?

AlphaMissense predicts ambiguous (score 0.4179) — an in-silico prediction, not a clinical call.

NES p.Arg285Trp

c.853C>T · rs1023410620 · VCV2331924

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4179 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Computational evidence

Protein change
AlphaMissense	0.4179	ambiguous · top 10% in NES
REVEL	0.572	indeterminate
SaProt	LLR -7.61	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.4	GERP 2.3, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 7,939 bp · p 0.0089 · regional, not allelic
Overall
CADD	32.0	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 0.005% Admixed American · 3/59,982 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000558% 9/1,613,544 alleles · very rare exomes 6/1,461,348 · genomes 3/152,196 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,994
African / African-American	0.004%	24,971
European (non-Finnish)	0.000254%	393,311

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.Arg285Trp
Coding: c.853C>T
MANE Select: NM_006617
dbSNP: rs1023410620
Type: single nucleotide variant
Location: chr1:156675271 (GRCh38)
Gene constraint: LOEUF 1.264 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.18
Residue 285: the if rod domain; the 'coil 2b' 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-arg285trp (accessed [today's date]).

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