Is TTC19 p.Leu219Ter (c.656T>G) pathogenic?

TTC19 p.Leu219Ter (c.656T>G) is classified Pathogenic in TTC19 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-11-14). Very rare (popmax 0.00852%, nfe); Associated with TTC19-related disorder.

What condition is associated with TTC19 p.Leu219Ter (c.656T>G)?

TTC19 p.Leu219Ter (c.656T>G) is associated with TTC19-related disorder, mitochondrial complex III deficiency nuclear type 2 (ClinVar).

How common is TTC19 p.Leu219Ter (c.656T>G) in the general population?

TTC19 p.Leu219Ter (c.656T>G) is very rare (popmax 0.00852%, nfe) (gnomAD).

TTC19 p.Leu219Ter

c.656T>G · rs747166010 · VCV31073

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00852%, nfe)

Conditions

TTC19-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 10
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.9, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00852% European (non-Finnish) · 100/1,174,178 alleles

Filtering AF 0.00711% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00663%

Overall 0.00628% 101/1,607,518 alleles · very rare exomes 95/1,455,342 · genomes 6/152,176 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00852%	11,742
African / African-American	0.00134%	74,778

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
Protein: p.Leu219Ter
Coding: c.656T>G
MANE Select: NM_017775
dbSNP: rs747166010
Type: single nucleotide variant
Location: chr17:16006548 (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

TTC19-related disorder

Also linked: mitochondrial complex III deficiency nuclear type 2

Similar variants

TTC19 p.Gln195Ter Pathogenic/Likely pathogenic ★★ same condition
TTC19 p.Leu185Pro Pathogenic/Likely 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
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-p-leu219ter (accessed [today's date]).

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