Is NEXN p.Ser665= (c.1995T>C) pathogenic?

NEXN p.Ser665= (c.1995T>C) is classified Likely benign in NEXN (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-12). Very rare (popmax 0.0022%, sas); Associated with dilated cardiomyopathy 1CC.

What condition is associated with NEXN p.Ser665= (c.1995T>C)?

NEXN p.Ser665= (c.1995T>C) is associated with dilated cardiomyopathy 1CC, cardiomyopathy, hypertrophic cardiomyopathy 20 (ClinVar).

How common is NEXN p.Ser665= (c.1995T>C) in the general population?

NEXN p.Ser665= (c.1995T>C) is very rare (popmax 0.0022%, sas) (gnomAD).

How is Familial isolated dilated cardiomyopathy inherited?

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

NEXN p.Ser665=

c.1995T>C · rs757311272 · VCV1118356

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

dilated cardiomyopathy 1CC

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.135	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.29	GERP -3.4, phastCons 0.38
Overall
CADD	7.994	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/90,896 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000683% 11/1,611,128 alleles · very rare exomes 11/1,458,864 · genomes 0/152,264 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,448
European (non-Finnish)	0.000764%	130,854

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.Ser665=
Coding: c.1995T>C
MANE Select: NM_144573
dbSNP: rs757311272
Type: single nucleotide variant
Location: chr1:77942796 (GRCh38)
Gene constraint: LOEUF 0.878 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.78
Residue 665: 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

dilated cardiomyopathy 1CC — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy hypertrophic cardiomyopathy 20

For Familial isolated dilated cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

NEXN p.Ser665Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
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.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-ser665 (accessed [today's date]).

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