Is TTC19 p.Met302Ile (c.906G>A) pathogenic?

TTC19 p.Met302Ile (c.906G>A) is classified Conflicting classifications of pathogenicity in TTC19 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-10-07). AlphaMissense: ambiguous (0.4094); Rare (popmax 0.154%, sas); Associated with mitochondrial complex III deficiency nuclear type 2.

What condition is associated with TTC19 p.Met302Ile (c.906G>A)?

TTC19 p.Met302Ile (c.906G>A) is associated with mitochondrial complex III deficiency nuclear type 2 (ClinVar).

How common is TTC19 p.Met302Ile (c.906G>A) in the general population?

TTC19 p.Met302Ile (c.906G>A) is rare (popmax 0.154%, sas) (gnomAD).

What do computational predictors say about TTC19 p.Met302Ile (c.906G>A)?

AlphaMissense predicts ambiguous (score 0.4094) — an in-silico prediction, not a clinical call.

TTC19 p.Met302Ile

c.906G>A · rs539229732 · VCV2054602

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4094 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.154%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

mitochondrial complex III deficiency nuclear type 2

Computational evidence

Protein change
AlphaMissense	0.4094	ambiguous
REVEL	0.174	moderately benign-leaning
SaProt	LLR -3.34	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 28 kb · p 0.9 · regional, not allelic
Overall
CADD	16.49	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 0.154% South Asian · 140/91,066 alleles

Filtering AF 0.133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.125%

Overall 0.00905% 146/1,614,118 alleles · rare exomes 139/1,461,816 · genomes 7/152,302 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.154%	650
Remaining individualsnot grpmax-eligible	0.008%	12,502
African / African-American	0.00133%	75,046

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.Met302Ile
Coding: c.906G>A
MANE Select: NM_017775
dbSNP: rs539229732
Type: single nucleotide variant
Location: chr17:16026614 (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.Met302fs Likely pathogenic ★ 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-met302ile (accessed [today's date]).

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