Is SCO2 p.Pro43Ala (c.127C>G) pathogenic?

SCO2 p.Pro43Ala (c.127C>G) is classified Uncertain significance in SCO2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-06). AlphaMissense: likely benign (0.0561); Ultra-rare (popmax 0.068%, afr); Associated with cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1.

How common is SCO2 p.Pro43Ala (c.127C>G) in the general population?

SCO2 p.Pro43Ala (c.127C>G) is ultra-rare (popmax 0.068%, afr) (gnomAD).

How is Fatal infantile cytochrome C oxidase deficiency inherited?

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

What do computational predictors say about SCO2 p.Pro43Ala (c.127C>G)?

AlphaMissense predicts likely benign (score 0.0561) — an in-silico prediction, not a clinical call.

SCO2 p.Pro43Ala

Q: What condition is associated with SCO2 p.Pro43Ala (c.127C>G)?

SCO2 p.Pro43Ala (c.127C>G) is associated with cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1, myopia 6 (ClinVar).

c.127C>G · rs147185850 · VCV1491943

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0561 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.068%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.0561	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -6.76	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 2.9	GERP -2.4, phastCons 1
Regional constraint	o/e 1.23	unconstrained · MANE · 797 bp · p 1.7e-05 · regional, not allelic
Overall
CADD	10.53	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.068% African / African-American · 51/75,000 alleles

Filtering AF 0.0531% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0478%

Overall 0.0038% 61/1,603,420 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.068%	1,471
Admixed American	0.0117%	8,572
Remaining individualsnot grpmax-eligible	0.0032%	31,207
European (non-Finnish)	8.48e-05%	1,179,802

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.Pro43Ala
Coding: c.127C>G
MANE Select: NM_005138
dbSNP: rs147185850
Type: single nucleotide variant
Location: chr22:50524285 (GRCh38)

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

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-pro43ala (accessed [today's date]).

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