NSMCE1

Chr 16

NSE1 component of SMC5/6 complex

Also known as: NSE1

NCBI Gene: 197370 ENSG00000169189 UniProt: Q8WV22 OMIM: 617263

NSMCE1 encodes a RING-type E3 ubiquitin ligase that functions within the SMC5-SMC6 complex to maintain genome integrity through DNA damage response and homologous recombination-mediated DNA repair. Mutations cause an autosomal recessive primary immunodeficiency characterized by growth retardation, developmental delay, facial dysmorphism, and increased susceptibility to infections. The gene shows tolerance to loss-of-function variants (pLI 0.00002, LOEUF 1.178), consistent with the recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

Enables protein dimerization activity and ubiquitin protein ligase activity. Involved in DNA damage response. Located in nucleoplasm. Part of Smc5-Smc6 complex. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.18

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.18LOEUF

pLI 0.000

Z-score 1.10

OE 0.68 (0.41–1.18)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.56Z-score

OE missense 0.88 (0.76–1.01)

141 obs / 160.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.68 (0.41–1.18)

0≤0.351.4

Missense OE?0.88 (0.76–1.01)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 9 / 13.3Missense obs/exp: 141 / 160.9Syn Z: 0.02

Background carrier burden — how many people carry a rare variant somewhere in NSMCE1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 170

348 rare PASS variants

Rare truncating (LoF)

1 in 2,100

53 rare PASS variants

Rare synonymous (reference)

1 in 290

127 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NSMCE1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 300	1 in 2,700
South Asian	~43k	1 in 130	1 in 1,800
Remaining (unassigned)	~30k	1 in 170	1 in 2,700
European (Finnish)	~27k	1 in 670	≈ 1 in 27,000
Admixed American	~22k	1 in 240	1 in 930
African / African American	~21k	1 in 150	1 in 3,200
East Asian	~20k	1 in 210	≈ 1 in 6,600
Ashkenazi Jewish	~13k	1 in 1,900	≈ 1 in 3,300
Middle Eastern	~2,884	1 in 190	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.