Is COA5 p.Ala53Pro (c.157G>C) pathogenic?

COA5 p.Ala53Pro (c.157G>C) is classified Pathogenic in COA5 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2011-04-08). AlphaMissense: likely pathogenic (0.9137); Very rare (popmax 8.48e-05%, nfe); Associated with cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3.

How common is COA5 p.Ala53Pro (c.157G>C) in the general population?

COA5 p.Ala53Pro (c.157G>C) is very rare (popmax 8.48e-05%, 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.

What do computational predictors say about COA5 p.Ala53Pro (c.157G>C)?

AlphaMissense predicts likely pathogenic (score 0.9137) — an in-silico prediction, not a clinical call.

COA5 p.Ala53Pro

Q: What condition is associated with COA5 p.Ala53Pro (c.157G>C)?

COA5 p.Ala53Pro (c.157G>C) is associated with cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3 (ClinVar).

c.157G>C · rs387907099 · VCV31087

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9137 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3

Computational evidence

Protein change
AlphaMissense	0.9137	likely pathogenic ✓ concordant with ClinVar
REVEL	0.581	indeterminate
SaProt	LLR -12.30	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 0.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,650 bp · p 0.81 · regional, not allelic
Overall
CADD	19.17	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,658 alleles

Overall 6.2e-05% 1/1,613,612 alleles · very rare exomes 1/1,461,318 · genomes 0/152,294 · 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: COA5
Protein: p.Ala53Pro
Coding: c.157G>C
MANE Select: NM_001008215
dbSNP: rs387907099
Type: single nucleotide variant
Location: chr2:98604134 (GRCh38)
Gene constraint: LOEUF 1.852 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.42
Residue 53: the chch domain; a UniProt-annotated variant site (in mc4dn9)

Full COA5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Fatal infantile cytochrome C oxidase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

COA5 p.Ala53Thr Uncertain significance ★★ ⚠ same residue
COA5 p.Ala53= Likely benign ★ same residue
COA5 p.Ala66Val Uncertain significance ★★ ⚠ same type
COA5 c.100-239A>G Benign ★★ same type
COA5 c.100-53A>G Benign ★★ same type
COA5 c.99+28G>A Benign ★★ same type
COA5 c.-130G>C Benign ★★ same type
COA5 c.-69C>G Likely benign ★★ same type

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/coa5-p-ala53pro (accessed [today's date]).

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