Is TTC19 p.Tyr299Cys (c.896A>G) pathogenic?

TTC19 p.Tyr299Cys (c.896A>G) is classified Uncertain significance in TTC19 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-02). AlphaMissense: likely benign (0.0686); Ultra-rare (popmax 0.0227%, afr).

How common is TTC19 p.Tyr299Cys (c.896A>G) in the general population?

TTC19 p.Tyr299Cys (c.896A>G) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about TTC19 p.Tyr299Cys (c.896A>G)?

AlphaMissense predicts likely benign (score 0.0686) — an in-silico prediction, not a clinical call.

TTC19 p.Tyr299Cys

c.896A>G · rs149178668 · VCV1359791

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0686 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0686	likely benign
REVEL	0.527	indeterminate
SaProt	LLR -8.35	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -3.4, phastCons 0.95
Regional constraint	o/e 0.99	unconstrained · MANE · 28 kb · p 0.9 · regional, not allelic
Overall
CADD	15.53	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 0.0227% African / African-American · 17/75,054 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.00112% 18/1,614,172 alleles · ultra-rare exomes 6/1,461,832 · genomes 12/152,340 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,415
European (non-Finnish)	8.47e-05%	1,179,994

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.Tyr299Cys
Coding: c.896A>G
MANE Select: NM_017775
dbSNP: rs149178668
Type: single nucleotide variant
Location: chr17:16026604 (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

Similar variants

TTC19 c.581+1G>C Pathogenic/Likely pathogenic ★★ same type
TTC19 p.Gln195Ter Pathogenic/Likely pathogenic ★★ same type
TTC19 p.Leu185Pro Pathogenic/Likely pathogenic ★★ same type
TTC19 p.Leu219Ter Pathogenic ★★ same type
TTC19 c.581+4A>C Uncertain significance ★★ same type
TTC19 c.994+3A>T Uncertain significance ★★ same type
TTC19 p.Ala122Thr Uncertain significance ★★ ⚠ same type
TTC19 p.Ala200Val Uncertain significance ★★ ⚠ same type

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-tyr299cys (accessed [today's date]).

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