Is NSMCE3 p.Ser49Arg (c.145A>C) pathogenic?

NSMCE3 p.Ser49Arg (c.145A>C) is classified Uncertain significance in NSMCE3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-20). AlphaMissense: likely pathogenic (0.884); Ultra-rare (popmax 0.0971%, sas).

How common is NSMCE3 p.Ser49Arg (c.145A>C) in the general population?

NSMCE3 p.Ser49Arg (c.145A>C) is ultra-rare (popmax 0.0971%, sas) (gnomAD).

What do computational predictors say about NSMCE3 p.Ser49Arg (c.145A>C)?

AlphaMissense predicts likely pathogenic (score 0.884) — an in-silico prediction, not a clinical call.

NSMCE3 p.Ser49Arg

c.145A>C · rs778266826 · VCV1500637

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.884 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0971%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.884	likely pathogenic
REVEL	0.137	moderately benign-leaning
SaProt	LLR -9.37	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 4.1	GERP 0.071, phastCons 0.99
Regional constraint	o/e 1.13	unconstrained · MANE · 911 bp · p 0.0086 · regional, not allelic
Overall
CADD	19.33	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0971% South Asian · 79/81,386 alleles

Filtering AF 0.0798% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0734%

Overall 0.00551% 84/1,525,024 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0971%	1,030
European (non-Finnish)	0.000438%	228,063

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.Ser49Arg
Coding: c.145A>C
MANE Select: NM_015307 · reported on NM_138704
dbSNP: rs778266826
Type: single nucleotide variant
Location: chr15:29269561 (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-ser49arg (accessed [today's date]).

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