Is NEXN p.Ser596Arg (c.1788T>G) pathogenic?

NEXN p.Ser596Arg (c.1788T>G) is classified Conflicting classifications of pathogenicity in NEXN (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-06-01). AlphaMissense: likely pathogenic (0.616); Ultra-rare (popmax 0.0557%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with NEXN p.Ser596Arg (c.1788T>G)?

NEXN p.Ser596Arg (c.1788T>G) is associated with Cardiovascular phenotype, cardiomyopathy, dilated cardiomyopathy 1CC (ClinVar).

How common is NEXN p.Ser596Arg (c.1788T>G) in the general population?

NEXN p.Ser596Arg (c.1788T>G) is ultra-rare (popmax 0.0557%, nfe) (gnomAD).

What do computational predictors say about NEXN p.Ser596Arg (c.1788T>G)?

AlphaMissense predicts likely pathogenic (score 0.616) — an in-silico prediction, not a clinical call.

NEXN p.Ser596Arg

c.1788T>G · rs199738750 · VCV47897

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.616 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0557%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.616	likely pathogenic
REVEL	0.3	indeterminate
SaProt	LLR -9.11	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.48	GERP -2.2, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 16 kb · p 0.011 · regional, not allelic
Overall
CADD	22.6	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 0.0557% European (non-Finnish) · 657/1,179,808 alleles

Filtering AF 0.0521% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0507%

Overall 0.0433% 698/1,613,866 alleles · ultra-rare exomes 655/1,461,668 · genomes 43/152,198 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0557%	1,796
Admixed American	0.035%	2,857
Remaining individualsnot grpmax-eligible	0.024%	4,167
African / African-American	0.00666%	15,004

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: NEXN
Protein: p.Ser596Arg
Coding: c.1788T>G
MANE Select: NM_144573
dbSNP: rs199738750
Type: single nucleotide variant
Location: chr1:77942589 (GRCh38)
Gene constraint: LOEUF 0.878 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.78
Residue 596: the ig-like domain; a UniProt-annotated variant site (in cmd2m; likely pathogenic)

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy dilated cardiomyopathy 1CC hypertrophic cardiomyopathy 20

Similar variants

NEXN p.Gly100Ter Pathogenic ★★ same condition
NEXN c.1473+1G>T Uncertain significance ★★ same condition
NEXN c.219+5T>G Uncertain significance ★★ same condition
NEXN c.299-3T>C Uncertain significance ★★ same condition
NEXN c.448-4A>G Uncertain significance ★★ same condition
NEXN c.865-4T>C Uncertain significance ★★ same condition
NEXN c.-10T>C Uncertain significance ★★ same condition
NEXN p.Ala266Gly 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/nexn-p-ser596arg (accessed [today's date]).

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