Is TTC19 c.994+3A>T pathogenic?

TTC19 c.994+3A>T is classified Uncertain significance in TTC19 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-10-24). Ultra-rare (popmax 0.0401%, eas); Associated with mitochondrial complex III deficiency nuclear type 2.

What condition is associated with TTC19 c.994+3A>T?

TTC19 c.994+3A>T is associated with mitochondrial complex III deficiency nuclear type 2 (ClinVar).

How common is TTC19 c.994+3A>T in the general population?

TTC19 c.994+3A>T is ultra-rare (popmax 0.0401%, eas) (gnomAD).

TTC19 c.994+3A>T

rs189614332 · VCV321949

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0401%, eas)

Conditions

mitochondrial complex III deficiency nuclear type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
Splice region	donor +3	donor splice region (+3, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	Δ0.34	donor gain · deltas
Constraint at this position
Conservation	phyloP 1.9	GERP -0.69, phastCons 1
Non-coding constraint	Z -0.15	1 kb window · o/e 1.01 · regional · uncalibrated
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0401% East Asian · 18/44,880 alleles

Filtering AF 0.0259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00118% 19/1,614,032 alleles · ultra-rare exomes 16/1,461,698 · genomes 3/152,334 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0401%	2,493
Remaining individualsnot grpmax-eligible	0.0016%	62,502

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.994+3A>T
MANE Select: NM_017775
dbSNP: rs189614332
Type: single nucleotide variant
Location: chr17:16026705 (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 p.Ala122Thr Uncertain significance ★★ ⚠ same condition
TTC19 p.Ala263Ser Uncertain significance ★★ ⚠ same condition
TTC19 p.Arg102Gly Uncertain significance ★★ ⚠ same condition
TTC19 p.Arg124His 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-994-plus-3a-t (accessed [today's date]).

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