Is COX5A p.Arg55Cys (c.163C>T) pathogenic?

COX5A p.Arg55Cys (c.163C>T) is classified Uncertain significance in COX5A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: ambiguous (0.4994); Ultra-rare (popmax 0.0164%, mid); Associated with mitochondrial complex IV deficiency, nuclear type 20.

What condition is associated with COX5A p.Arg55Cys (c.163C>T)?

COX5A p.Arg55Cys (c.163C>T) is associated with mitochondrial complex IV deficiency, nuclear type 20 (ClinVar).

How common is COX5A p.Arg55Cys (c.163C>T) in the general population?

COX5A p.Arg55Cys (c.163C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

How is Isolated cytochrome C oxidase deficiency inherited?

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

What do computational predictors say about COX5A p.Arg55Cys (c.163C>T)?

AlphaMissense predicts ambiguous (score 0.4994) — an in-silico prediction, not a clinical call.

COX5A p.Arg55Cys

c.163C>T · VCV4277769

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4994 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

mitochondrial complex IV deficiency, nuclear type 20

Computational evidence

Protein change
AlphaMissense	0.4994	ambiguous
REVEL	0.77	pathogenic-leaning
SaProt	LLR -16.16	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 14 kb · p 0.01 · regional, not allelic
Overall
CADD	32.0	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.0013% 21/1,613,928 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
East Asian	0.0111%	8,977
Remaining individualsnot grpmax-eligible	0.0048%	20,827
South Asian	0.00329%	30,363
Finnishnot grpmax-eligible	0.00156%	64,010
European (non-Finnish)	0.000678%	147,497

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: COX5A
Protein: p.Arg55Cys
Coding: c.163C>T
MANE Select: NM_004255
Type: single nucleotide variant
Location: chr15:74929170 (GRCh38)
Gene constraint: LOEUF 0.82 · pLI 0.65 (gnomAD)
Structure: AlphaFold pLDDT 88.21 · 3 PDB

Full COX5A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial complex IV deficiency, nuclear type 20 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Isolated cytochrome C oxidase deficiency (Orphanet):

Inheritance: Autosomal recessive, Mitochondrial inheritance

Similar variants

COX5A p.Arg107Cys Pathogenic same condition
COX5A p.Ile89Ser Pathogenic same condition
COX5A p.Ser25Cys Likely benign ★★ same type
COX5A p.Ala13Thr Uncertain significance ★ ⚠ same type
COX5A p.Ala32Asp Uncertain significance ★ ⚠ same type
COX5A p.Ala32Thr Uncertain significance ★ ⚠ same type
COX5A p.Ala54Gly Uncertain significance ★ ⚠ same type
COX5A p.Arg107Ser Uncertain significance ★ ⚠ 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/cox5a-p-arg55cys (accessed [today's date]).

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