Is NEXN p.Ser503= (c.1509C>T) pathogenic?

NEXN p.Ser503= (c.1509C>T) is classified Likely benign in NEXN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-09). Very rare (popmax 0.0022%, sas); Associated with dilated cardiomyopathy 1CC.

What condition is associated with NEXN p.Ser503= (c.1509C>T)?

NEXN p.Ser503= (c.1509C>T) is associated with dilated cardiomyopathy 1CC, hypertrophic cardiomyopathy 20 (ClinVar).

How common is NEXN p.Ser503= (c.1509C>T) in the general population?

NEXN p.Ser503= (c.1509C>T) 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.Ser503=

c.1509C>T · rs757578397 · VCV2165131

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 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	0.569	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP -3.4, phastCons 0.001
Overall
CADD	8.517	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,000 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000248% 4/1,613,174 alleles · very rare exomes 3/1,461,148 · genomes 1/152,026 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,592
South Asiangrpmax	0.0022%	45,500
European (non-Finnish)	8.48e-05%	1,179,510

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser503=
Coding: c.1509C>T
MANE Select: NM_144573
dbSNP: rs757578397
Type: single nucleotide variant
Location: chr1:77942058 (GRCh38)
Gene constraint: LOEUF 0.878 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.78
Residue 503: a UniProt-annotated variant site (in cmd2m; likely pathogenic); the 'disordered' region

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: 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.Ser503Asn Uncertain significance ★★ ⚠ same residue
NEXN p.Ser503Thr Uncertain significance ★ ⚠ 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.-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-ser503 (accessed [today's date]).

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