ARCN1

Chr 11AD

archain 1 coat protein complex I subunit delta

Also known as: COPD, SRMMD, SSMG

NCBI Gene: 372 ENSG00000095139 UniProt: P48444 OMIM: 600820

ARCN1 encodes a component of the coatomer complex that is essential for protein transport between the endoplasmic reticulum and Golgi apparatus and maintains Golgi structural integrity. Mutations cause autosomal dominant short stature-micrognathia syndrome. This gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.10), indicating that haploinsufficiency is likely not tolerated in the general population.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene maps in a region, which include the mixed lineage leukemia and Friend leukemia virus integration 1 genes, where multiple disease-associated chromosome translocations occur. It is an intracellular protein. Archain sequences are well conserved among eukaryotes and this protein may play a fundamental role in eukaryotic cell biology. It has similarities to heat shock proteins and clathrin-associated proteins, and may be involved in vesicle structure or trafficking. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.101 OMIM phenotype

Clinical Summary— ARCN1

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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.

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ClinVar Variants

32 unique Pathogenic / Likely Pathogenic· 137 VUS of 327 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.10LOEUF

pLI 1.000

Z-score 5.05

OE 0.00 (0.00–0.10)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

2.08Z-score

OE missense 0.65 (0.58–0.74)

186 obs / 284.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.10)

0≤0.351.4

Missense OE?0.65 (0.58–0.74)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 0 / 29.6Missense obs/exp: 186 / 284.9Syn Z: -0.09

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongARCN1-related microcephalic dwarfismLOFAD

This gene — mechanism propensity

0.2798th %ile

GOF

0.2796th %ile

LOF

0.75top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 94% of P/LP variants are LoF · LOEUF 0.10 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFIzumi et al. (2016) report 4 individuals with 3 different ARCN1 variants: one nonsense and two frameshifts, all predicted to undergo nonsense mediated decay. Subject 1 has c. 260C>A [p.Ser87*], inheritance unknown. Subject 2 has a de novo ARCN1 frameshift: (c.633del [p.Val212Trpfs*15], and an additi1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 27476655 ↗

ClinVar Variant Classifications

327 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23

Likely Pathogenic9

VUS137

Likely Benign104

Benign25

Conflicting15

Pathogenic

Likely Pathogenic

137

VUS

104

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	23	0	0	0	23
Likely Pathogenic	7	1	1	0	9
VUS	1	132	4	0	137
Likely Benign	0	11	36	57	104
Benign	0	3	15	7	25
Conflicting	—				15
Total	31	147	56	64	313

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

View in ClinVar →

27 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap ARCN1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →