Is TTC19 c.*226T>C pathogenic?

TTC19 c.226T>C is classified Benign/Likely benign in TTC19 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-10-08). Common (popmax 6.5%, afr) — too common for a highly-penetrant pathogenic allele; Associated with mitochondrial complex III deficiency nuclear type 2.

What condition is associated with TTC19 c.*226T>C?

TTC19 c.*226T>C is associated with mitochondrial complex III deficiency nuclear type 2 (ClinVar).

TTC19 c.*226T>C

Q: How common is TTC19 c.*226T>C in the general population?

TTC19 c.*226T>C is common (popmax 6.5%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs73981412 · VCV891500

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 6.5%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

mitochondrial complex III deficiency nuclear type 2

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 -0.047	GERP -0.66
Non-coding constraint	Z 1.49	1 kb window · o/e 0.89 · regional · uncalibrated
Overall
CADD	3.579	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.5% African / African-American · 3,586/55,128 alleles

Filtering AF 6.33% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.25%

Overall 0.65% 3,942/606,076 alleles · common exomes 1,165/453,804 · genomes 2,777/152,272 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.5%	15
Remaining individualsnot grpmax-eligible	0.549%	182
Admixed American	0.337%	297
Middle Eastern	0.302%	331
South Asian	0.0121%	8,237
European (non-Finnish)	0.0114%	8,793

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: TTC19
Coding: c.*226T>C
MANE Select: NM_017775
dbSNP: rs73981412
Type: single nucleotide variant
Location: chr17:16027748 (GRCh38)
Gene constraint: LOEUF 1.049 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.28

Full TTC19 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial complex III deficiency nuclear type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TTC19 p.Gln195Ter Pathogenic/Likely pathogenic ★★ same condition
TTC19 p.Leu185Pro Pathogenic/Likely pathogenic ★★ same condition
TTC19 p.Leu219Ter Pathogenic ★★ same condition
TTC19 c.581+4A>C Uncertain significance ★★ same condition
TTC19 c.994+3A>T Uncertain significance ★★ same condition
TTC19 p.Ala122Thr Uncertain significance ★★ ⚠ same condition
TTC19 p.Ala263Ser Uncertain significance ★★ ⚠ same condition
TTC19 p.Arg102Gly 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/ttc19-c-star-226t-c (accessed [today's date]).

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