Is TTC19 p.Phe204Leu (c.612C>G) pathogenic?

TTC19 p.Phe204Leu (c.612C>G) is classified Conflicting classifications of pathogenicity in TTC19 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-08). AlphaMissense: likely pathogenic (0.997); Rare (popmax 0.136%, sas); Associated with Inborn genetic diseases.

What condition is associated with TTC19 p.Phe204Leu (c.612C>G)?

TTC19 p.Phe204Leu (c.612C>G) is associated with Inborn genetic diseases, mitochondrial complex III deficiency nuclear type 2 (ClinVar).

How common is TTC19 p.Phe204Leu (c.612C>G) in the general population?

TTC19 p.Phe204Leu (c.612C>G) is rare (popmax 0.136%, sas) (gnomAD).

What do computational predictors say about TTC19 p.Phe204Leu (c.612C>G)?

AlphaMissense predicts likely pathogenic (score 0.997) — an in-silico prediction, not a clinical call.

TTC19 p.Phe204Leu

c.612C>G · rs544027755 · VCV215307

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.997 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.136%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.997	likely pathogenic · top 1% in TTC19
REVEL	0.406	indeterminate
SaProt	LLR -10.71	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 28 kb · p 0.9 · regional, not allelic
Overall
CADD	27.0	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 0.136% South Asian · 124/91,054 alleles

Filtering AF 0.117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.109%

Overall 0.00824% 133/1,613,334 alleles · rare exomes 128/1,461,176 · genomes 5/152,158 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.136%	734
Middle Eastern	0.0168%	5,966
Remaining individualsnot grpmax-eligible	0.0064%	15,618
European (non-Finnish)	0.000339%	294,872

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.Phe204Leu
Coding: c.612C>G
MANE Select: NM_017775
dbSNP: rs544027755
Type: single nucleotide variant
Location: chr17:16006504 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mitochondrial complex III deficiency nuclear type 2

Similar variants

TTC19 p.Phe204Ser Uncertain significance ★ ⚠ 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.Ala200Val 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-phe204leu (accessed [today's date]).

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