Is SCO2 p.Pro134fs (c.401_402del) pathogenic?

SCO2 p.Pro134fs (c.401402del) is classified Pathogenic/Likely pathogenic in SCO2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-29). Very rare (popmax 0.0011%, nfe); Associated with cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1.

How common is SCO2 p.Pro134fs (c.401_402del) in the general population?

SCO2 p.Pro134fs (c.401_402del) is very rare (popmax 0.0011%, nfe) (gnomAD).

How is Fatal infantile cytochrome C oxidase deficiency inherited?

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

SCO2 p.Pro134fs

Q: What condition is associated with SCO2 p.Pro134fs (c.401_402del)?

SCO2 p.Pro134fs (c.401_402del) is associated with cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1, myopia 6 (ClinVar).

c.401_402del · rs762796240 · VCV2737058

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Conditions

cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (2 of 2) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 2.6, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,180,024 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00093% 15/1,613,464 alleles · very rare exomes 13/1,461,212 · genomes 2/152,252 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,494
European (non-Finnish)grpmax	0.0011%	90,771
South Asian	0.0011%	91,084

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: SCO2
Protein: p.Pro134fs
Coding: c.401_402del
MANE Select: NM_005138
dbSNP: rs762796240
Type: Deletion
Location: chr22:50524010 (GRCh38)
Gene constraint: LOEUF 1.761 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.14 · 1 PDB
Residue 134: a β-strand; the thioredoxin domain

Full SCO2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: myopia 6

For Fatal infantile cytochrome C oxidase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

SCO2 p.Pro134His Uncertain significance ★★ ⚠ same residue
SCO2 p.Leu188fs Likely pathogenic ★ same condition
SCO2 p.Leu71fs Likely pathogenic ★ same condition
SCO2 p.Ala74Asp Uncertain significance ★★ ⚠ same condition
SCO2 p.Arg120Trp Uncertain significance ★★ ⚠ same condition
SCO2 p.Arg206Cys Uncertain significance ★★ ⚠ same condition
SCO2 p.Arg255Gln Uncertain significance ★★ ⚠ same condition
SCO2 p.Gly129Asp 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/sco2-p-pro134fs (accessed [today's date]).

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