Is TTC19 p.Arg333Gln (c.998G>A) pathogenic?

TTC19 p.Arg333Gln (c.998G>A) is classified Uncertain significance in TTC19 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-16). AlphaMissense: likely benign (0.0707); Ultra-rare (popmax 0.0164%, mid); Associated with mitochondrial complex III deficiency nuclear type 2.

What condition is associated with TTC19 p.Arg333Gln (c.998G>A)?

TTC19 p.Arg333Gln (c.998G>A) is associated with mitochondrial complex III deficiency nuclear type 2 (ClinVar).

How common is TTC19 p.Arg333Gln (c.998G>A) in the general population?

TTC19 p.Arg333Gln (c.998G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about TTC19 p.Arg333Gln (c.998G>A)?

AlphaMissense predicts likely benign (score 0.0707) — an in-silico prediction, not a clinical call.

TTC19 p.Arg333Gln

c.998G>A · rs1483019285 · VCV889941

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0707 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial complex III deficiency nuclear type 2

Computational evidence

Protein change
AlphaMissense	0.0707	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -4.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.30	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 4.3	GERP -0.069, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 28 kb · p 0.9 · regional, not allelic
Overall
CADD	16.29	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00329%

Overall 0.00384% 62/1,613,574 alleles · ultra-rare exomes 58/1,461,662 · genomes 4/151,912 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
European (non-Finnish)	0.00466%	21,451
East Asian	0.00446%	22,442
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,590
Remaining individualsnot grpmax-eligible	0.0032%	31,240
African / African-American	0.00134%	74,776

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.Arg333Gln
Coding: c.998G>A
MANE Select: NM_017775
dbSNP: rs1483019285
Type: single nucleotide variant
Location: chr17:16027377 (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.Arg333Ter Conflicting classifications of pathogenicity ★ same residue
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

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-arg333gln (accessed [today's date]).

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