Is NES p.Arg196Ser (c.586C>A) pathogenic?

NES p.Arg196Ser (c.586C>A) is classified Uncertain significance in NES (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-18). AlphaMissense: likely pathogenic (0.6841); Very rare (popmax 0.00176%, nfe).

How common is NES p.Arg196Ser (c.586C>A) in the general population?

NES p.Arg196Ser (c.586C>A) is very rare (popmax 0.00176%, nfe) (gnomAD).

What do computational predictors say about NES p.Arg196Ser (c.586C>A)?

AlphaMissense predicts likely pathogenic (score 0.6841) — an in-silico prediction, not a clinical call.

NES p.Arg196Ser

c.586C>A · rs550134632 · VCV2538152

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6841 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00176%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6841	likely pathogenic · top 5% in NES
REVEL	0.558	indeterminate
SaProt	LLR -10.67	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 7,939 bp · p 0.0089 · regional, not allelic
Overall
CADD	29.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00176% European (non-Finnish) · 20/1,137,954 alleles

Filtering AF 0.00115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000933%

Overall 0.00146% 22/1,501,832 alleles · very rare exomes 22/1,349,954 · genomes 0/151,878 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00176%	56,898
Remaining individualsnot grpmax-eligible	0.00173%	57,932
African / African-American	0.00146%	68,376

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.Arg196Ser
Coding: c.586C>A
MANE Select: NM_006617
dbSNP: rs550134632
Type: single nucleotide variant
Location: chr1:156676679 (GRCh38)
Gene constraint: LOEUF 1.264 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 49.18
Residue 196: 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.Arg196His Uncertain significance ★ ⚠ same residue
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

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-arg196ser (accessed [today's date]).

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