SAMD12

Chr 8AD

sterile alpha motif domain containing 12

Also known as: BAFME, BAFME1, FAME, FAME1, FCMTE1, MEBA

NCBI Gene: 401474 ENSG00000177570 UniProt: Q8N8I0 OMIM: 618073

SAMD12 encodes a protein predicted to function in cell surface receptor protein tyrosine kinase signaling at the cytoplasmic side of the plasma membrane. Mutations cause familial adult myoclonic epilepsy type 1, which follows autosomal dominant inheritance with adult onset as the name suggests. The gene shows tolerance to loss-of-function variants (pLI 0.001, LOEUF 1.14), indicating that complete loss of protein function may not be the primary disease mechanism.

OMIM ResearchSummary from RefSeq, OMIM

Predicted to be involved in cell surface receptor protein tyrosine kinase signaling pathway. Predicted to be active in cytoplasmic side of plasma membrane. Implicated in familial adult myoclonic epilepsy 1. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 1.141 OMIM phenotype

Clinical Summary— SAMD12

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 29 VUS of 51 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.14LOEUF

pLI 0.001

Z-score 1.26

OE 0.58 (0.32–1.14)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.08Z-score

OE missense 1.02 (0.88–1.20)

109 obs / 106.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.58 (0.32–1.14)

0≤0.351.4

Missense OE?1.02 (0.88–1.20)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 6 / 10.4Missense obs/exp: 109 / 106.6Syn Z: -0.39

This gene — mechanism propensity

0.6744th %ile

GOF

0.6540th %ile

LOF

0.3842th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

51 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

VUS29

Likely Benign3

Pathogenic

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Total
Pathogenic	0	3	3
Likely Pathogenic	0	0	0
VUS	28	1	29
Likely Benign	3	0	3
Benign	0	0	0
Total	31	4	35

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

View in ClinVar →

58 pathogenic / likely-pathogenic (of 69) ClinVar copy-number / structural variants overlap SAMD12 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →