Is NEXN p.Pro646= (c.1938A>C) pathogenic?

NEXN p.Pro646= (c.1938A>C) is classified Likely benign in NEXN (ClinVar, Single submitter, 1 submitter; last evaluated 2018-02-07). Very rare (popmax 0.0022%, sas).

How common is NEXN p.Pro646= (c.1938A>C) in the general population?

NEXN p.Pro646= (c.1938A>C) is very rare (popmax 0.0022%, sas) (gnomAD).

NEXN p.Pro646=

c.1938A>C · rs1571176052 · VCV724573

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.063	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -8.1
Overall
CADD	5.939	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,070 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000124% 2/1,613,834 alleles · very rare exomes 2/1,461,530 · genomes 0/152,304 · 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.Pro646=
Coding: c.1938A>C
MANE Select: NM_144573
dbSNP: rs1571176052
Type: single nucleotide variant
Location: chr1:77942739 (GRCh38)
Gene constraint: LOEUF 0.878 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.78
Residue 646: the ig-like domain; a UniProt-annotated variant site (in cmd2m; likely pathogenic)

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

Similar variants

NEXN p.Pro646Gln Uncertain significance ★ ⚠ same residue
NEXN p.Gly100Ter Pathogenic ★★ same type
NEXN c.1473+1G>T Uncertain significance ★★ same type
NEXN c.219+5T>G Uncertain significance ★★ same type
NEXN c.299-3T>C Uncertain significance ★★ same type
NEXN c.448-4A>G Uncertain significance ★★ same type
NEXN c.865-4T>C Uncertain significance ★★ same type
NEXN c.-10T>C Uncertain significance ★★ same type

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-pro646 (accessed [today's date]).

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