SMCHD1

Chr 18ADDigenic dominant

structural maintenance of chromosomes flexible hinge domain containing 1

Also known as: BAMS, FSHD2

NCBI Gene: 23347ENSG00000101596UniProt: A6NHR9

This gene encodes a protein which contains a hinge region domain found in members of the SMC (structural maintenance of chromosomes) protein family. [provided by RefSeq, Dec 2011]

Primary Disease Associations & Inheritance

Bosma arhinia microphthalmia syndromeMIM #603457
AD
Facioscapulohumeral muscular dystrophy 2, digenicMIM #158901
Digenic dominant
1951
ClinVar variants
50
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— SMCHD1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
50 Pathogenic / Likely Pathogenic· 284 VUS of 1951 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.15LOEUF
pLI 1.000
Z-score 8.56
OE 0.09 (0.05–0.15)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.63Z-score
OE missense 0.67 (0.63–0.71)
634 obs / 948.8 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.09 (0.05–0.15)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.67 (0.63–0.71)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.94
0≤1.21.6
LoF obs/exp: 9 / 102.5Missense obs/exp: 634 / 948.8Syn Z: 0.80

ClinVar Variant Classifications

1951 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29
Likely Pathogenic21
VUS284
Likely Benign126
Benign4
Conflicting1
29
Pathogenic
21
Likely Pathogenic
284
VUS
126
Likely Benign
4
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
0
22
0
29
Likely Pathogenic
14
0
7
0
21
VUS
4
251
23
6
284
Likely Benign
0
5
65
56
126
Benign
0
0
3
1
4
Conflicting
—1
Total2525612063465

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SMCHD1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SMCHD1-related isolated arhinia/Bosma arhinia syndrome

definitive
ADUndeterminedAltered Gene Product Structure
Dev. DisordersEye
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Bosma arhinia microphthalmia syndrome

MIM #603457

Molecular basis of disorder known

Autosomal dominant

Facioscapulohumeral muscular dystrophy 2, digenic

MIM #158901

Molecular basis of disorder known

Digenic dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Facioscapulohumeral muscular dystrophy.
Sacconi S et al.·Biochim Biophys Acta
2015Review
Facioscapulohumeral Muscular Dystrophies.
Wagner KR·Continuum (Minneap Minn)
2019Review
Facioscapulohumeral Muscular Dystrophy.
Statland JM et al.·Continuum (Minneap Minn)
2016Review
Genotype-phenotype correlations in FSHD.
Zernov N et al.·BMC Med Genomics
2019Review
SMCHD1 genetic variants in type 2 facioscapulohumeral dystrophy and challenges in predicting pathogenicity and disease penetrance.
Gérard L et al.·Eur J Hum Genet
2025
Autosomal dominant in cis D4Z4 repeat array duplication alleles in facioscapulohumeral dystrophy.
Lemmers RJLF et al.·Brain
2024
Clinical report of Bosma arhinia microphthalmia syndrome with a new variant on SMCHD1 gene. A case report.
Atencia Goñi J et al.·Endocrinol Diabetes Nutr (Engl Ed)
2024Review
HOX epimutations driven by maternal SMCHD1/LRIF1 haploinsufficiency trigger homeotic transformations in genetically wildtype offspring.
Xue S et al.·Nat Commun
2022
Non-coding autoimmune risk variant defines role for ICOS in T peripheral helper cell development.
Kim T et al.·Nat Commun
2024
Nasal Construction in Congenital Arhinia Due to Novel SMCHD1 Gene Variant.
Bargiela M et al.·J Craniofac Surg
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Facioscapulohumeral Muscular Dystrophy Type 2

An 18-month Prospective Natural History Study to Gain Insight Into FSHD2 Pathophysiology and Disease Progression

RECRUITING
NCT06079567Phase NACentre Hospitalier Universitaire de NiceStarted 2023-10-03
Validation of new COMs for FSHD2 patients

External Resources

Links to major genomics databases and tools