Is TTC19 p.Ala256Thr (c.766G>A) pathogenic?

TTC19 p.Ala256Thr (c.766G>A) is classified Uncertain significance in TTC19 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-08-11). AlphaMissense: likely pathogenic (0.7255); Very rare (popmax 0.000424%, nfe); Associated with mitochondrial complex III deficiency nuclear type 2.

What condition is associated with TTC19 p.Ala256Thr (c.766G>A)?

TTC19 p.Ala256Thr (c.766G>A) is associated with mitochondrial complex III deficiency nuclear type 2 (ClinVar).

How common is TTC19 p.Ala256Thr (c.766G>A) in the general population?

TTC19 p.Ala256Thr (c.766G>A) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about TTC19 p.Ala256Thr (c.766G>A)?

AlphaMissense predicts likely pathogenic (score 0.7255) — an in-silico prediction, not a clinical call.

TTC19 p.Ala256Thr

c.766G>A · rs1042684635 · VCV547995

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7255 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial complex III deficiency nuclear type 2

Computational evidence

Protein change
AlphaMissense	0.7255	likely pathogenic
REVEL	0.934	strongly pathogenic-leaning
SaProt	LLR -13.92	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 28 kb · p 0.9 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000424% European (non-Finnish) · 5/1,179,878 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,908 alleles · very rare exomes 5/1,461,654 · genomes 0/152,254 · joint denominator

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.Ala256Thr
Coding: c.766G>A
MANE Select: NM_017775
dbSNP: rs1042684635
Type: single nucleotide variant
Location: chr17:16025106 (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-p-ala256thr (accessed [today's date]).

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