Is TTC19 c.312+43C>A pathogenic?

TTC19 c.312+43C>A is classified Benign in TTC19 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-09-10). Common (popmax 55.6%, mid) — too common for a highly-penetrant pathogenic allele; Associated with mitochondrial complex III deficiency nuclear type 2.

What condition is associated with TTC19 c.312+43C>A?

TTC19 c.312+43C>A is associated with mitochondrial complex III deficiency nuclear type 2 (ClinVar).

TTC19 c.312+43C>A

Q: How common is TTC19 c.312+43C>A in the general population?

TTC19 c.312+43C>A is common (popmax 55.6%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs758853 · VCV1342856

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 55.6%, mid) — 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
Splice region	donor +43	near-intronic (+43 nt from the splice site)
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.59	GERP -0.76
Non-coding constraint	Z 2.78	1 kb window · o/e 0.83 · regional · uncalibrated
Overall
CADD	6.517	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 55.6% Middle Eastern · 2,450/4,404 alleles

Filtering AF 53.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 53%

Overall 49.2% 781,519/1,588,498 alleles · common exomes 716,624/1,436,362 · genomes 64,895/152,136 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	62.7%	2
Middle Easterngrpmax	55.6%	2
Finnishnot grpmax-eligible	55.3%	2
European (non-Finnish)	53%	2
Amishnot grpmax-eligible	52.1%	2
Remaining individualsnot grpmax-eligible	48.5%	2
Admixed American	39.3%	3
South Asian	38.5%	3
African / African-American	22.5%	4
East Asian	13.6%	7

Ashkenazi Jewish 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: TTC19
Coding: c.312+43C>A
MANE Select: NM_017775
dbSNP: rs758853
Type: single nucleotide variant
Location: chr17:16000288 (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-312-plus-43c-a (accessed [today's date]).

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