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.

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndromeMIM #614739

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · Leigh syndrome · AR · ClinGen 2021
Definitive · 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome · AR · G2P

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.63

LOEUF

LOF

Mechanism· G2P

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

Background carrier burden — how many people carry a rare variant somewhere in SERAC1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 57

734 rare PASS variants

Rare truncating (LoF)

1 in 290

160 rare PASS variants

Rare synonymous (reference)

1 in 180

258 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SERAC1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 85	1 in 270
South Asian	~43k	1 in 77	1 in 280
Remaining (unassigned)	~30k	1 in 70	1 in 230
European (Finnish)	~27k	1 in 270	1 in 3,800
Admixed American	~22k	1 in 73	1 in 500
African / African American	~21k	1 in 68	1 in 270
East Asian	~20k	1 in 110	1 in 550
Ashkenazi Jewish	~13k	1 in 580	1 in 960
Middle Eastern	~2,884	1 in 140	≈ 1 in 950

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 13 of 16 coding exons well covered in gnomAD exomes; exons 3, 4, 9 marginal. Genomes: all 16.? see exons ↓