Is TTC19 p.Gln336Ter (c.1006C>T) pathogenic?

TTC19 p.Gln336Ter (c.1006C>T) is classified Uncertain significance in TTC19 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-17). Very rare (popmax 0.00924%, nfe).

How common is TTC19 p.Gln336Ter (c.1006C>T) in the general population?

TTC19 p.Gln336Ter (c.1006C>T) is very rare (popmax 0.00924%, nfe) (gnomAD).

TTC19 p.Gln336Ter

c.1006C>T · rs369088691 · VCV2172473

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00924%, nfe)

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	escapes	premature termination codon in the last exon (10 of 10) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Pangolin	Δ0.50	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 5	GERP 1.9, phastCons 1
Overall
CADD	40.0	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 0.00924% European (non-Finnish) · 109/1,179,924 alleles

Filtering AF 0.00782% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00728%

Overall 0.0083% 134/1,613,900 alleles · very rare exomes 123/1,461,744 · genomes 11/152,156 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0234%	4,268
Remaining individualsnot grpmax-eligible	0.0144%	6,942
European (non-Finnish)grpmax	0.00924%	10,825
African / African-American	0.00133%	74,918

Finnish 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
Protein: p.Gln336Ter
Coding: c.1006C>T
MANE Select: NM_017775
dbSNP: rs369088691
Type: single nucleotide variant
Location: chr17:16027385 (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

Similar variants

TTC19 p.Gln336Pro Uncertain significance ★ ⚠ same residue
TTC19 c.581+1G>C Pathogenic/Likely pathogenic ★★ same type
TTC19 p.Gln195Ter Pathogenic/Likely pathogenic ★★ same type
TTC19 p.Leu185Pro Pathogenic/Likely pathogenic ★★ same type
TTC19 p.Leu219Ter Pathogenic ★★ same type
TTC19 c.581+4A>C Uncertain significance ★★ same type
TTC19 c.994+3A>T Uncertain significance ★★ same type
TTC19 p.Ala122Thr Uncertain significance ★★ ⚠ same type

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-gln336ter (accessed [today's date]).

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