Is NEXN p.Phe35Ser (c.104T>C) pathogenic?

NEXN p.Phe35Ser (c.104T>C) is classified Uncertain significance in NEXN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-18). AlphaMissense: likely pathogenic (0.9859); Ultra-rare (popmax 0.0134%, eas); Associated with Cardiovascular phenotype.

What condition is associated with NEXN p.Phe35Ser (c.104T>C)?

NEXN p.Phe35Ser (c.104T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is NEXN p.Phe35Ser (c.104T>C) in the general population?

NEXN p.Phe35Ser (c.104T>C) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about NEXN p.Phe35Ser (c.104T>C)?

AlphaMissense predicts likely pathogenic (score 0.9859) — an in-silico prediction, not a clinical call.

NEXN p.Phe35Ser

c.104T>C · rs1208062139 · VCV2537892

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9859 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9859	likely pathogenic · top 2% in NEXN
REVEL	0.524	indeterminate
SaProt	LLR -15.06	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 11 kb · p 0.069 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,794 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00395%

Overall 0.000806% 13/1,613,390 alleles · ultra-rare exomes 12/1,461,334 · genomes 1/152,056 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,466
European (non-Finnish)	0.000593%	168,533

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.Phe35Ser
Coding: c.104T>C
MANE Select: NM_144573
dbSNP: rs1208062139
Type: single nucleotide variant
Location: chr1:77917642 (GRCh38)
Gene constraint: LOEUF 0.878 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.78
Residue 35: 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.Phe35Val 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-phe35ser (accessed [today's date]).

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