Is NEXN p.Pro217= (c.651A>G) pathogenic?

NEXN p.Pro217= (c.651A>G) is classified Likely benign in NEXN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-04-28). Very rare (popmax 0.00267%, afr); Associated with Cardiovascular phenotype.

What condition is associated with NEXN p.Pro217= (c.651A>G)?

NEXN p.Pro217= (c.651A>G) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1CC, hypertrophic cardiomyopathy 20 (ClinVar).

How common is NEXN p.Pro217= (c.651A>G) in the general population?

NEXN p.Pro217= (c.651A>G) is very rare (popmax 0.00267%, afr) (gnomAD).

NEXN p.Pro217=

c.651A>G · rs1403113011 · VCV2025112

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

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	0.013	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.59	GERP -4.4
Overall
CADD	0.54	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,924 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000744% 12/1,613,822 alleles · very rare exomes 10/1,461,634 · genomes 2/152,188 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,462
European (non-Finnish)	0.000848%	117,993

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.Pro217=
Coding: c.651A>G
MANE Select: NM_144573
dbSNP: rs1403113011
Type: single nucleotide variant
Location: chr1:77926575 (GRCh38)
Gene constraint: LOEUF 0.878 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.78

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

Also linked: dilated cardiomyopathy 1CC hypertrophic cardiomyopathy 20

Similar variants

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.448-4A>G Uncertain significance ★★ same condition
NEXN c.-10T>C Uncertain significance ★★ same condition
NEXN p.Ala266Gly Uncertain significance ★★ ⚠ same condition
NEXN p.Ala343Val 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-pro217 (accessed [today's date]).

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