SERAC1

Chr 6AR

serine active site containing 1

NCBI Gene: 84947 ENSG00000122335 UniProt: Q96JX3 OMIM: 614725

This gene encodes a phosphatidylglycerol remodeling protein located at mitochondria-endoplasmic reticulum interfaces that mediates phospholipid exchange and is essential for mitochondrial function and intracellular cholesterol trafficking. Biallelic mutations cause 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL), inherited in an autosomal recessive pattern. The pathogenesis involves loss of protein function leading to disrupted mitochondrial metabolism and energy production.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a phosphatidylglycerol remodeling protein found at the interface of mitochondria and endoplasmic reticula, where it mediates phospholipid exchange. The encoded protein plays a major role in mitochondrial function and intracellular cholesterol trafficking. Defects in this gene are a cause of 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL). Two transcript variants, one protein-coding and the other non-protein coding, have been found for this gene. [provided by RefSeq, Aug 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.631 OMIM phenotype

Clinical Summary— SERAC1

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

59 unique Pathogenic / Likely Pathogenic· 170 VUS of 518 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SERAC1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.63LOEUF

pLI 0.000

Z-score 3.39

OE 0.41 (0.28–0.63)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.49Z-score

OE missense 0.78 (0.70–0.86)

278 obs / 357.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.41 (0.28–0.63)

0≤0.351.4

Missense OE?0.78 (0.70–0.86)

0≤0.61.4

Synonymous OE?0.83

0≤1.21.6

LoF obs/exp: 16 / 38.8Missense obs/exp: 278 / 357.3Syn Z: 1.49

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSERAC1-related 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6358th %ile

GOF

0.6053th %ile

LOF

0.2777th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

518 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29

Likely Pathogenic30

VUS170

Likely Benign204

Benign51

Conflicting17

Pathogenic

Likely Pathogenic

170

VUS

204

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	24	3	2	0	29
Likely Pathogenic	21	6	3	0	30
VUS	6	142	18	4	170
Likely Benign	1	10	120	73	204
Benign	0	3	45	3	51
Conflicting	—				17
Total	52	164	188	80	501

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

View in ClinVar →

28 pathogenic / likely-pathogenic (of 33) ClinVar copy-number / structural variants overlap SERAC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →