Is COA8 c.321+2T>A pathogenic?

COA8 c.321+2T>A is classified Likely pathogenic in COA8 (ClinVar, No assertion criteria, 1 submitter). Absent from gnomAD v4.1; Associated with mitochondrial complex IV deficiency, nuclear type 17.

What condition is associated with COA8 c.321+2T>A?

COA8 c.321+2T>A is associated with mitochondrial complex IV deficiency, nuclear type 17 (ClinVar).

How common is COA8 c.321+2T>A in the general population?

COA8 c.321+2T>A is absent from gnomAD v4.1 (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.

COA8 c.321+2T>A

rs2507478587 · VCV2428493

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

mitochondrial complex IV deficiency, nuclear type 17

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function
Splicing
Splice region	donor +2	canonical splice dinucleotide (donor +2) · inside the BP7-excluded zone
SpliceAI	Δ0.98	donor loss · deltas
Pangolin	Δ0.24	gain · loss 0.00 · SpliceAI calls loss · independent
Constraint at this position
Conservation	phyloP 4.7	GERP 0.38, phastCons 1
Non-coding constraint	Z 1.59	1 kb window · o/e 0.89 · regional · uncalibrated
Overall
CADD	26.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: COA8
Coding: c.321+2T>A
MANE Select: NM_001370595
dbSNP: rs2507478587
Type: single nucleotide variant
Location: chr14:103571822 (GRCh38)
Gene constraint: LOEUF 1.305 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.19

Full COA8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial complex IV deficiency, nuclear type 17 — 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

COA8 p.Arg66Ter Pathogenic ★★ same condition
COA8 p.Arg34Leu Uncertain significance ★★ ⚠ same condition
COA8 p.Arg66Gln Uncertain significance ★★ ⚠ same condition
COA8 p.Asp36Tyr Uncertain significance ★★ ⚠ same condition
COA8 p.Glu145Lys Uncertain significance ★★ ⚠ same condition
COA8 p.Glu33Lys Uncertain significance ★★ ⚠ same condition
COA8 p.Pro14Ser Uncertain significance ★★ ⚠ same condition
COA8 p.Pro58Thr 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/coa8-c-321-plus-2t-a (accessed [today's date]).

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