Is SERAC1 p.Ser458= (c.1374C>T) pathogenic?

SERAC1 p.Ser458= (c.1374C>T) is classified Conflicting classifications of pathogenicity in SERAC1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-07-12). Very rare (popmax 0.00958%, nfe); Associated with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome.

How common is SERAC1 p.Ser458= (c.1374C>T) in the general population?

SERAC1 p.Ser458= (c.1374C>T) is very rare (popmax 0.00958%, nfe) (gnomAD).

How is MEGDEL syndrome inherited?

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

SERAC1 p.Ser458=

Q: What condition is associated with SERAC1 p.Ser458= (c.1374C>T)?

SERAC1 p.Ser458= (c.1374C>T) is associated with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (ClinVar).

c.1374C>T · rs138536589 · VCV2050891

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00958%, 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/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.26	donor loss, 29 bp away · masked 0 · deltas
Pangolin	Δ0.21	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -2.2	GERP -3.2
Overall
CADD	4.142	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00958% European (non-Finnish) · 113/1,179,984 alleles

Filtering AF 0.00809% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0076%

Overall 0.00787% 127/1,614,062 alleles · very rare exomes 116/1,461,820 · genomes 11/152,242 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00958%	10,442
African / African-American	0.00667%	15,003
Admixed American	0.005%	20,001
Remaining individualsnot grpmax-eligible	0.0048%	20,835
East Asian	0.00446%	22,437
South Asian	0.0011%	91,080

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.Ser458=
Coding: c.1374C>T
MANE Select: NM_032861
dbSNP: rs138536589
Type: single nucleotide variant
Location: chr6:158117756 (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 c.1403+1G>C Pathogenic ★★ same condition
SERAC1 p.Arg148Ter Pathogenic ★★ same condition
SERAC1 p.Arg368Ter Pathogenic ★★ same condition
SERAC1 p.Arg387Ter Pathogenic/Likely pathogenic ★★ same condition
SERAC1 p.Arg447Ter Pathogenic ★★ same condition
SERAC1 p.Arg68Ter Pathogenic/Likely pathogenic ★★ same condition
SERAC1 p.Gln376Ter Pathogenic ★★ same condition
SERAC1 p.Ser498Thr Pathogenic/Likely pathogenic ★★ 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-ser458 (accessed [today's date]).

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