Is NSMCE3 p.Phe227= (c.681T>C) pathogenic?

NSMCE3 p.Phe227= (c.681T>C) is classified Likely benign in NSMCE3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-23). Ultra-rare (popmax 0.0187%, sas).

How common is NSMCE3 p.Phe227= (c.681T>C) in the general population?

NSMCE3 p.Phe227= (c.681T>C) is ultra-rare (popmax 0.0187%, sas) (gnomAD).

NSMCE3 p.Phe227=

c.681T>C · rs375328693 · VCV2781545

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -3.6	GERP -3.8
Overall
CADD	1.353	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% South Asian · 17/91,068 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00976%

Overall 0.00287% 42/1,461,892 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0187%	5,357
European (non-Finnish)	0.00203%	49,168
Remaining individualsnot grpmax-eligible	0.0016%	62,506

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.Phe227=
Coding: c.681T>C
MANE Select: NM_015307 · reported on NM_138704
dbSNP: rs375328693
Type: single nucleotide variant
Location: chr15:29269025 (GRCh38)

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

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-phe227 (accessed [today's date]).

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