Is SERAC1 p.Pro423fs (c.1266dup) pathogenic?

SERAC1 p.Pro423fs (c.1266dup) is classified Pathogenic in SERAC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-25). Very rare (popmax 8.48e-05%, nfe); Associated with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome.

What condition is associated with SERAC1 p.Pro423fs (c.1266dup)?

SERAC1 p.Pro423fs (c.1266dup) is associated with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (ClinVar).

How common is SERAC1 p.Pro423fs (c.1266dup) in the general population?

SERAC1 p.Pro423fs (c.1266dup) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is MEGDEL syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

SERAC1 p.Pro423fs

c.1266dup · rs927446955 · VCV1961244

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.51	GERP -1.7

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,904 alleles

Overall 6.2e-05% 1/1,613,896 alleles · very rare exomes 1/1,461,610 · genomes 0/152,286 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SERAC1
Protein: p.Pro423fs
Coding: c.1266dup
MANE Select: NM_032861
dbSNP: rs927446955
Type: Duplication
Location: chr6:158119070 (GRCh38)
Gene constraint: LOEUF 0.681 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.66

Full SERAC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MEGDEL syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

SERAC1 p.Ala609fs Pathogenic/Likely pathogenic ★★ same condition
SERAC1 p.Gly89fs Pathogenic/Likely pathogenic ★★ same condition
SERAC1 p.Leu550fs Pathogenic/Likely pathogenic ★★ same condition
SERAC1 c.1502-24dup Benign/Likely benign ★★ same condition
SERAC1 c.266-48dup Benign ★★ same condition
SERAC1 c.1166+2dup Likely pathogenic ★ same condition
SERAC1 p.Tyr375Ter Likely pathogenic ★ same condition
SERAC1 p.Asp633fs Uncertain significance ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/serac1-p-pro423fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown