Is FASTKD2 p.Arg75= (c.225A>G) pathogenic?

FASTKD2 p.Arg75= (c.225A>G) is classified Uncertain significance in FASTKD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-17). Very rare (popmax 0.00341%, amr); Associated with mitochondrial complex IV deficiency, nuclear type 1.

What condition is associated with FASTKD2 p.Arg75= (c.225A>G)?

FASTKD2 p.Arg75= (c.225A>G) is associated with mitochondrial complex IV deficiency, nuclear type 1, combined oxidative phosphorylation deficiency 44 (ClinVar).

How common is FASTKD2 p.Arg75= (c.225A>G) in the general population?

FASTKD2 p.Arg75= (c.225A>G) is very rare (popmax 0.00341%, amr) (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.

FASTKD2 p.Arg75=

c.225A>G · rs374830420 · VCV333801

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00341%, amr)

Conditions

mitochondrial complex IV deficiency, nuclear type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.74	GERP 0.58, phastCons 0.005
Overall
CADD	5.907	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00341% Admixed American · 2/58,630 alleles

Filtering AF 0.000693% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000542%

Overall 0.00137% 22/1,601,634 alleles · very rare exomes 22/1,449,266 · genomes 0/152,368 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00808%	12,378
Admixed Americangrpmax	0.00341%	29,315
East Asian	0.00224%	44,642
European (non-Finnish)	0.00119%	83,753

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: FASTKD2
Protein: p.Arg75=
Coding: c.225A>G
MANE Select: NM_001136193
dbSNP: rs374830420
Type: single nucleotide variant
Location: chr2:206766918 (GRCh38)
Gene constraint: LOEUF 1.203 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.39

Full FASTKD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial complex IV deficiency, nuclear type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: combined oxidative phosphorylation deficiency 44

For Isolated cytochrome C oxidase deficiency (Orphanet):

Inheritance: Autosomal recessive, Mitochondrial inheritance

Similar variants

FASTKD2 c.882-1G>A Pathogenic/Likely pathogenic ★★ same condition
FASTKD2 c.991-2A>G Likely pathogenic ★★ same condition
FASTKD2 p.Arg290Ter Pathogenic ★★ same condition
FASTKD2 p.Arg358Ter Pathogenic/Likely pathogenic ★★ same condition
FASTKD2 p.Arg432Ter Pathogenic/Likely pathogenic ★★ same condition
FASTKD2 p.Cys283Ter Pathogenic/Likely pathogenic ★★ same condition
FASTKD2 p.Gln564Ter Pathogenic/Likely pathogenic ★★ same condition
FASTKD2 p.Trp302Ter Pathogenic/Likely pathogenic ★★ 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/fastkd2-p-arg75 (accessed [today's date]).

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