Is NEXN p.Ser50Pro (c.148T>C) pathogenic?

NEXN p.Ser50Pro (c.148T>C) is classified Uncertain significance in NEXN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-13). AlphaMissense: likely pathogenic (0.9356); Very rare (popmax 8.48e-05%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with NEXN p.Ser50Pro (c.148T>C)?

NEXN p.Ser50Pro (c.148T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is NEXN p.Ser50Pro (c.148T>C) in the general population?

NEXN p.Ser50Pro (c.148T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about NEXN p.Ser50Pro (c.148T>C)?

AlphaMissense predicts likely pathogenic (score 0.9356) — an in-silico prediction, not a clinical call.

NEXN p.Ser50Pro

c.148T>C · VCV3878961

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9356 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9356	likely pathogenic · top 6% in NEXN
REVEL	0.16	moderately benign-leaning
SaProt	LLR -11.26	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 0.81, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 11 kb · p 0.069 · regional, not allelic
Overall
CADD	24.2	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 8.48e-05% European (non-Finnish) · 1/1,179,006 alleles

Overall 6.2e-05% 1/1,612,318 alleles · very rare exomes 1/1,460,190 · genomes 0/152,128 · 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.Ser50Pro
Coding: c.148T>C
MANE Select: NM_144573
Type: single nucleotide variant
Location: chr1:77917686 (GRCh38)
Gene constraint: LOEUF 0.878 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.78
Residue 50: the 'disordered' region

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

Similar variants

NEXN p.Ser50Ala Uncertain significance ★★ ⚠ same residue
NEXN c.448-4A>G Uncertain significance ★★ same condition
NEXN p.Ala266Gly Uncertain significance ★★ ⚠ same condition
NEXN p.Ala343Val Uncertain significance ★★ ⚠ same condition
NEXN p.Ala476Thr Uncertain significance ★★ ⚠ same condition
NEXN p.Ala486Gly Uncertain significance ★★ ⚠ same condition
NEXN p.Ala500Ser Uncertain significance ★★ ⚠ same condition
NEXN p.Ala500Thr 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-ser50pro (accessed [today's date]).

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