Is NSMCE3 p.Pro65Leu (c.194C>T) pathogenic?

NSMCE3 p.Pro65Leu (c.194C>T) is classified Uncertain significance in NSMCE3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-12-10). AlphaMissense: likely benign (0.0836); Ultra-rare (popmax 0.0123%, afr).

How common is NSMCE3 p.Pro65Leu (c.194C>T) in the general population?

NSMCE3 p.Pro65Leu (c.194C>T) is ultra-rare (popmax 0.0123%, afr) (gnomAD).

What do computational predictors say about NSMCE3 p.Pro65Leu (c.194C>T)?

AlphaMissense predicts likely benign (score 0.0836) — an in-silico prediction, not a clinical call.

NSMCE3 p.Pro65Leu

c.194C>T · rs776727229 · VCV1426978

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0836 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0836	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -6.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 2.1	GERP 0.13, phastCons 0.11
Regional constraint	o/e 1.13	unconstrained · MANE · 911 bp · p 0.0086 · regional, not allelic
Overall
CADD	14.42	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0123% African / African-American · 9/73,372 alleles

Filtering AF 0.00635% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00476%

Overall 0.000815% 13/1,595,116 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0123%	8,152
East Asian	0.00458%	21,826
South Asian	0.00112%	89,640
European (non-Finnish)	8.53e-05%	1,172,774

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.Pro65Leu
Coding: c.194C>T
MANE Select: NM_015307 · reported on NM_138704
dbSNP: rs776727229
Type: single nucleotide variant
Location: chr15:29269512 (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-pro65leu (accessed [today's date]).

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