Is NSMCE3 p.Arg133= (c.399C>T) pathogenic?

NSMCE3 p.Arg133= (c.399C>T) is classified Likely benign in NSMCE3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-01). Very rare (popmax 0.000508%, nfe).

How common is NSMCE3 p.Arg133= (c.399C>T) in the general population?

NSMCE3 p.Arg133= (c.399C>T) is very rare (popmax 0.000508%, nfe) (gnomAD).

NSMCE3 p.Arg133=

c.399C>T · rs905897571 · VCV1539975

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -0.85, phastCons 1
Overall
CADD	12.17	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000508% European (non-Finnish) · 6/1,180,044 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00041% 6/1,461,886 alleles · very rare

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: NSMCE3
Protein: p.Arg133=
Coding: c.399C>T
MANE Select: NM_138704
dbSNP: rs905897571
Type: single nucleotide variant
Location: chr15:29269307 (GRCh38)
Structure: AlphaFold pLDDT 76.08 · 5 PDB
Residue 133: the mage domain; an α-helix; the 'interaction with nsmce1' region

Full NSMCE3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NSMCE3 p.Ala32= Likely benign ★★ same type
NSMCE3 p.Asn272Asp Uncertain significance ★ ⚠ same type
NSMCE3 p.Asp164Asn Uncertain significance ★ ⚠ same type
NSMCE3 p.Leu202Met Uncertain significance ★ ⚠ same type
NSMCE3 p.Ser11Cys Uncertain significance ★ ⚠ same type
NSMCE3 p.Ala76= Likely benign ★ same type
NSMCE3 p.Arg17= Likely benign ★ same type
NSMCE3 p.Arg31= Likely benign ★ 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/nsmce3-p-arg133 (accessed [today's date]).

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