Is CYC1 p.Arg33= (c.99T>G) pathogenic?

CYC1 p.Arg33= (c.99T>G) is classified Benign in CYC1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). Common (popmax 99.7%, eas) — too common for a highly-penetrant pathogenic allele; Associated with mitochondrial complex III deficiency nuclear type 6.

What condition is associated with CYC1 p.Arg33= (c.99T>G)?

CYC1 p.Arg33= (c.99T>G) is associated with mitochondrial complex III deficiency nuclear type 6 (ClinVar).

CYC1 p.Arg33=

Q: How common is CYC1 p.Arg33= (c.99T>G) in the general population?

CYC1 p.Arg33= (c.99T>G) is common (popmax 99.7%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.99T>G · rs11541475 · VCV379959

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 99.7%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

mitochondrial complex III deficiency nuclear type 6

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 2.4	GERP 0.28, phastCons 1
Overall
CADD	14.13	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 99.7% East Asian · 28,988/29,084 alleles

Filtering AF 98.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 98.3%

Overall 90.7% 1,093,275/1,205,102 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	99.7%	1
South Asian	96%	1
Amishnot grpmax-eligible	94.3%	1
Finnishnot grpmax-eligible	92.6%	1
Ashkenazi Jewishnot grpmax-eligible	92.3%	1
Admixed American	91.9%	1
European (non-Finnish)	91.4%	1
Remaining individualsnot grpmax-eligible	90.8%	1
Middle Eastern	89.8%	1
African / African-American	71.7%	1

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: CYC1
Protein: p.Arg33=
Coding: c.99T>G
MANE Select: NM_001916
dbSNP: rs11541475
Type: single nucleotide variant
Location: chr8:144095198 (GRCh38)
Gene constraint: LOEUF 0.583 · pLI 0.85 (gnomAD)
Structure: AlphaFold pLDDT 86.37 · 5 PDB

Full CYC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial complex III deficiency nuclear type 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CYC1 p.Ala4Val Uncertain significance ★★ ⚠ same condition
CYC1 p.Arg285Gln Uncertain significance ★★ ⚠ same condition
CYC1 c.873+7G>A Benign/Likely benign ★★ same condition
CYC1 p.Met76Val Benign ★★ same condition
CYC1 p.Leu215Phe Pathogenic ★ same condition
CYC1 p.Trp96Cys Pathogenic same condition
CYC1 p.Arg317Trp Uncertain significance ⚠ same condition
CYC1 c.772+19_772+20del 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/cyc1-p-arg33 (accessed [today's date]).

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