Is COQ2 p.Pro46Ser (c.136C>T) pathogenic?

COQ2 p.Pro46Ser (c.136C>T) is classified Conflicting classifications of pathogenicity in COQ2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-09-03). AlphaMissense: likely benign (0.0605); Ultra-rare (popmax 0.0504%, nfe); Associated with coenzyme Q10 deficiency, primary, 1.

What condition is associated with COQ2 p.Pro46Ser (c.136C>T)?

COQ2 p.Pro46Ser (c.136C>T) is associated with coenzyme Q10 deficiency, primary, 1, multiple system atrophy 1, susceptibility to, mitochondrial disease (ClinVar).

How common is COQ2 p.Pro46Ser (c.136C>T) in the general population?

COQ2 p.Pro46Ser (c.136C>T) is ultra-rare (popmax 0.0504%, nfe) (gnomAD).

What do computational predictors say about COQ2 p.Pro46Ser (c.136C>T)?

AlphaMissense predicts likely benign (score 0.0605) — an in-silico prediction, not a clinical call.

COQ2 p.Pro46Ser

c.136C>T · rs767013819 · VCV1285203

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0605 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0504%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

coenzyme Q10 deficiency, primary, 1

Computational evidence

Protein change
AlphaMissense	0.0605	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -7.08	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.24	GERP -3.2
Regional constraint	o/e 1.03	unconstrained · MANE · 21 kb · p 0.51 · regional, not allelic
Overall
CADD	0.03	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 0.0504% European (non-Finnish) · 571/1,132,040 alleles

Filtering AF 0.047% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0456%

Overall 0.0399% 604/1,512,102 alleles · ultra-rare exomes 562/1,360,052 · genomes 42/152,050 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0504%	1,983
Remaining individualsnot grpmax-eligible	0.0291%	3,434
Admixed American	0.0128%	7,817
African / African-American	0.0102%	9,824
Ashkenazi Jewishnot grpmax-eligible	0.00367%	27,242
Finnishnot grpmax-eligible	0.00358%	27,894

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: COQ2
Protein: p.Pro46Ser
Coding: c.136C>T
MANE Select: NM_001358921
dbSNP: rs767013819
Type: single nucleotide variant
Location: chr4:83284629 (GRCh38)
Gene constraint: LOEUF 1.032 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.64

Full COQ2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

coenzyme Q10 deficiency, primary, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: multiple system atrophy 1, susceptibility to mitochondrial disease

Similar variants

COQ2 p.Pro46= Likely benign ★★ same residue
COQ2 p.Pro46Leu Likely benign ★★ same residue
COQ2 p.Arg123Cys Likely pathogenic ★★ same condition
COQ2 p.Arg147His Pathogenic/Likely pathogenic ★★ same condition
COQ2 p.Ser96Asn Pathogenic ★★ same condition
COQ2 p.Trp24Ter Likely pathogenic ★★ same condition
COQ2 c.-26G>C Uncertain significance ★★ same condition
COQ2 p.Ala100Thr 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/coq2-p-pro46ser (accessed [today's date]).

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