Is NEXN p.Ser15Pro (c.43T>C) pathogenic?

NEXN p.Ser15Pro (c.43T>C) is classified Uncertain significance in NEXN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-16). AlphaMissense: ambiguous (0.4193); Very rare (popmax 0.000678%, nfe); Associated with cardiomyopathy.

What condition is associated with NEXN p.Ser15Pro (c.43T>C)?

NEXN p.Ser15Pro (c.43T>C) is associated with cardiomyopathy (ClinVar).

How common is NEXN p.Ser15Pro (c.43T>C) in the general population?

NEXN p.Ser15Pro (c.43T>C) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about NEXN p.Ser15Pro (c.43T>C)?

AlphaMissense predicts ambiguous (score 0.4193) — an in-silico prediction, not a clinical call.

NEXN p.Ser15Pro

c.43T>C · rs2526781130 · VCV2691225

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4193 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.4193	ambiguous
REVEL	0.194	benign-leaning
SaProt	LLR -6.22	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.55 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.1	GERP 2.2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 11 kb · p 0.069 · regional, not allelic
Overall
CADD	23.4	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 0.000678% European (non-Finnish) · 8/1,179,288 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,613,092 alleles · very rare exomes 8/1,460,798 · genomes 0/152,294 · joint denominator

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.Ser15Pro
Coding: c.43T>C
MANE Select: NM_144573
dbSNP: rs2526781130
Type: single nucleotide variant
Location: chr1:77917581 (GRCh38)
Gene constraint: LOEUF 0.878 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.78
Residue 15: the 'disordered' region

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

Disease context

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

Similar variants

NEXN p.Ser15= Likely benign ★ same residue
NEXN c.299-3T>C Uncertain significance ★★ same condition
NEXN c.865-4T>C Uncertain significance ★★ same condition
NEXN p.Arg273His Uncertain significance ★★ ⚠ same condition
NEXN p.Arg306Cys Uncertain significance ★★ ⚠ same condition
NEXN p.Arg306His Uncertain significance ★★ ⚠ same condition
NEXN p.Arg397Gln Uncertain significance ★★ ⚠ same condition
NEXN p.Arg412Gly 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-ser15pro (accessed [today's date]).

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