Is TTC19 p.Pro253Leu (c.758C>T) pathogenic?

TTC19 p.Pro253Leu (c.758C>T) is classified Conflicting classifications of pathogenicity in TTC19 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.108); Low-frequency (popmax 2.93%, afr); Associated with mitochondrial complex III deficiency nuclear type 2.

What condition is associated with TTC19 p.Pro253Leu (c.758C>T)?

TTC19 p.Pro253Leu (c.758C>T) is associated with mitochondrial complex III deficiency nuclear type 2 (ClinVar).

How common is TTC19 p.Pro253Leu (c.758C>T) in the general population?

TTC19 p.Pro253Leu (c.758C>T) is low-frequency (popmax 2.93%, afr) (gnomAD).

What do computational predictors say about TTC19 p.Pro253Leu (c.758C>T)?

AlphaMissense predicts likely benign (score 0.108) — an in-silico prediction, not a clinical call.

TTC19 p.Pro253Leu

c.758C>T · rs78882347 · VCV321947

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.108 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.93%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial complex III deficiency nuclear type 2

Computational evidence

Protein change
AlphaMissense	0.108	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -9.03	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 28 kb · p 0.9 · regional, not allelic
Overall
CADD	18.59	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.93% African / African-American · 2,200/74,982 alleles

Filtering AF 2.83% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.79%

Overall 0.152% 2,460/1,613,836 alleles · low-frequency exomes 1,225/1,461,626 · genomes 1,235/152,210 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.93%	34
Remaining individualsnot grpmax-eligible	0.216%	463
Middle Eastern	0.198%	505
Admixed American	0.125%	800
South Asian	0.00988%	10,119
European (non-Finnish)	0.00237%	42,137
East Asian	0.00223%	44,870

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.Pro253Leu
Coding: c.758C>T
MANE Select: NM_017775
dbSNP: rs78882347
Type: single nucleotide variant
Location: chr17:16025098 (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.Pro253= Likely benign ★ 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-pro253leu (accessed [today's date]).

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