SIMC1

Chr 5

SUMO interacting motifs containing 1

Also known as: C5orf25, OOMA1, PLEIAD

NCBI Gene: 375484 ENSG00000170085 UniProt: Q8NDZ2 OMIM: 618102

SIMC1 encodes a protein that enables SUMO polymer binding and peptidase inhibitor activity, and forms complexes required to recruit the SMC5-SMC6 complex to PML nuclear bodies for viral restriction. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe intellectual disability, seizures, and progressive brain atrophy. The gene shows high constraint against loss-of-function variants, indicating intolerance to protein-truncating mutations.

OMIM ResearchSummary from RefSeq, UniProt

Enables SUMO polymer binding activity and peptidase inhibitor activity. Located in PML body and sarcomere. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.91

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.91LOEUF

pLI 0.000

Z-score 1.87

OE 0.56 (0.36–0.91)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.54Z-score

OE missense 0.90 (0.80–1.01)

202 obs / 224.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.56 (0.36–0.91)

0≤0.351.4

Missense OE?0.90 (0.80–1.01)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 12 / 21.3Missense obs/exp: 202 / 224.6Syn Z: 0.08

Background carrier burden — how many people carry a rare variant somewhere in SIMC1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 35

1,059 rare PASS variants

Rare truncating (LoF)

1 in 670

129 rare PASS variants

Rare synonymous (reference)

1 in 100

424 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SIMC1. 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 47	1 in 530
South Asian	~43k	1 in 40	1 in 630
Remaining (unassigned)	~30k	1 in 34	1 in 640
European (Finnish)	~27k	1 in 200	1 in 2,700
Admixed American	~22k	1 in 41	1 in 1,900
African / African American	~21k	1 in 46	1 in 1,300
East Asian	~20k	1 in 55	1 in 1,300
Ashkenazi Jewish	~13k	1 in 150	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 38	none seen

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.

Exome coverage (gnomAD): 9 of 10 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: 9 of 10 (exon 1 below).? see exons ↓