SEC61A1

Chr 3AD

SEC61 translocon subunit alpha 1

Also known as: ADTKD5, CVID15, HNFJ4, HSEC61, SEC61, SEC61A

NCBI Gene: 29927 ENSG00000058262 UniProt: P61619 OMIM: 609213

The protein encoded by this gene belongs to the SECY/SEC61- alpha family. It appears to play a crucial role in the insertion of secretory and membrane polypeptides into the endoplasmic reticulum. This protein found to be tightly associated with membrane-bound ribosomes, either directly or through adaptor proteins. This gene encodes an alpha subunit of the heteromeric SEC61 complex, which also contains beta and gamma subunits. [provided by RefSeq, Jul 2008]

GeneReviews OMIM Research

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.293 OMIM phenotypes

Clinical Summary— SEC61A1

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Gene-Disease Validity (ClinGen)

SEC61A1 deficiency · ADModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

9 unique Pathogenic / Likely Pathogenic· 122 VUS of 363 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SEC61A1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.29LOEUF

pLI 0.987

Z-score 4.21

OE 0.11 (0.05–0.29)

Highly constrained

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

Missense Constraint?

4.06Z-score

OE missense 0.32 (0.27–0.38)

92 obs / 284.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.11 (0.05–0.29)

0≤0.351.4

Missense OE?0.32 (0.27–0.38)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 3 / 26.3Missense obs/exp: 92 / 284.9Syn Z: -0.30

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedSEC61A1-related tubulo-interstitial and glomerulocystic kidney disease with anemiaOTHERAD

This gene — mechanism propensity

0.6064th %ile

GOF

0.4974th %ile

LOF

0.56top 25%

The Badonyi & Marsh model scores dominant-negative highest, but genomic evidence most strongly supports loss-of-function (haploinsufficiency) as the primary mechanism.

LOF1 literature citation · LOEUF 0.29

Literature Evidence

LOFHeterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.1

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 27392076 ↗

ClinVar Variant Classifications

363 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic4

VUS122

Likely Benign180

Benign31

Conflicting5

Pathogenic

Likely Pathogenic

122

VUS

180

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	4	0	0	5
Likely Pathogenic	0	4	0	0	4
VUS	4	101	14	3	122
Likely Benign	0	1	88	91	180
Benign	0	0	27	4	31
Conflicting	—				5
Total	5	110	129	98	347

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap SEC61A1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →