Is NEXN p.Pro499= (c.1497T>C) pathogenic?

NEXN p.Pro499= (c.1497T>C) is classified Likely benign in NEXN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-12). Very rare (popmax 0.00267%, afr); Associated with Cardiovascular phenotype.

What condition is associated with NEXN p.Pro499= (c.1497T>C)?

NEXN p.Pro499= (c.1497T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is NEXN p.Pro499= (c.1497T>C) in the general population?

NEXN p.Pro499= (c.1497T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

NEXN p.Pro499=

c.1497T>C · VCV3919102

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.029	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.91, phastCons 1
Overall
CADD	10.27	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,890 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,168 alleles · very rare exomes 0/1,461,020 · genomes 2/152,148 · 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.Pro499=
Coding: c.1497T>C
MANE Select: NM_144573
Type: single nucleotide variant
Location: chr1:77942046 (GRCh38)
Gene constraint: LOEUF 0.878 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.78
Residue 499: 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

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

Similar variants

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
NEXN p.Arg127Cys 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-pro499 (accessed [today's date]).

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