Is COX6B1 p.Pro83Ser (c.247C>T) pathogenic?

COX6B1 p.Pro83Ser (c.247C>T) is classified Uncertain significance in COX6B1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-01-30). AlphaMissense: likely benign (0.2458); Ultra-rare (popmax 0.0365%, nfe); Associated with mitochondrial complex IV deficiency, nuclear type 7.

What condition is associated with COX6B1 p.Pro83Ser (c.247C>T)?

COX6B1 p.Pro83Ser (c.247C>T) is associated with mitochondrial complex IV deficiency, nuclear type 7, mitochondrial complex IV deficiency, nuclear type 1 (ClinVar).

How common is COX6B1 p.Pro83Ser (c.247C>T) in the general population?

COX6B1 p.Pro83Ser (c.247C>T) is ultra-rare (popmax 0.0365%, nfe) (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 COX6B1 p.Pro83Ser (c.247C>T)?

AlphaMissense predicts likely benign (score 0.2458) — an in-silico prediction, not a clinical call.

COX6B1 p.Pro83Ser

c.247C>T · rs111638609 · VCV214276

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2458 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0365%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial complex IV deficiency, nuclear type 7

Computational evidence

Protein change
AlphaMissense	0.2458	likely benign
REVEL	0.698	pathogenic-leaning
SaProt	LLR -11.72	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 0.76, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 7,400 bp · p 0.0019 · regional, not allelic
Overall
CADD	23.5	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 0.0365% European (non-Finnish) · 431/1,179,950 alleles

Filtering AF 0.0337% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0325%

Overall 0.0288% 465/1,613,942 alleles · ultra-rare exomes 445/1,461,782 · genomes 20/152,160 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0365%	2,738
Remaining individualsnot grpmax-eligible	0.0288%	3,471
Middle Eastern	0.0164%	6,084
Admixed American	0.01%	9,997
African / African-American	0.00934%	10,704
South Asian	0.0022%	45,545

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: COX6B1
Protein: p.Pro83Ser
Coding: c.247C>T
MANE Select: NM_001863
dbSNP: rs111638609
Type: single nucleotide variant
Location: chr19:35658633 (GRCh38)
Gene constraint: LOEUF 0.421 · pLI 0.99 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 95.15 · 3 PDB

Full COX6B1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial complex IV deficiency, nuclear type 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mitochondrial complex IV deficiency, nuclear type 1

For Isolated cytochrome C oxidase deficiency (Orphanet):

Inheritance: Autosomal recessive, Mitochondrial inheritance

Similar variants

COX6B1 p.Pro83= Likely benign ★★ same residue
COX6B1 p.Arg20Cys Likely pathogenic ★★ same condition
COX6B1 p.Glu6Asp Uncertain significance ★★ ⚠ same condition
COX6B1 p.Gly84Arg Uncertain significance ★★ ⚠ same condition
COX6B1 p.Thr71Ile Uncertain significance ★★ ⚠ same condition
COX6B1 p.Val53Met Uncertain significance ★★ ⚠ same condition
COX6B1 c.107-16A>G Benign/Likely benign ★★ same condition
COX6B1 c.-11-8G>A Likely benign ★★ 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/cox6b1-p-pro83ser (accessed [today's date]).

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