Is TTC8 p.Ala277fs (c.826_829dup) pathogenic?

TTC8 p.Ala277fs (c.826829dup) is classified Pathogenic in TTC8 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-06-03). Very rare (popmax 0.00017%, nfe); Associated with Bardet-Biedl syndrome.

What condition is associated with TTC8 p.Ala277fs (c.826_829dup)?

TTC8 p.Ala277fs (c.826_829dup) is associated with Bardet-Biedl syndrome, inherited retinal dystrophy (ClinVar).

How common is TTC8 p.Ala277fs (c.826_829dup) in the general population?

TTC8 p.Ala277fs (c.826_829dup) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Bardet-Biedl syndrome inherited?

Typically Autosomal recessive, Oligogenic (Orphanet). A genetic counselor can assess individual risk for a family.

TTC8 p.Ala277fs

c.826_829dup · VCV3250252

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

Bardet-Biedl syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.19	GERP -1.1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,254 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,612,756 alleles · very rare exomes 2/1,460,494 · genomes 0/152,262 · 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: TTC8
Protein: p.Ala277fs
Coding: c.826_829dup
MANE Select: NM_144596
Type: Duplication
Location: chr14:88861246 (GRCh38)
Gene constraint: LOEUF 0.8 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.48

Full TTC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Bardet-Biedl syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: inherited retinal dystrophy

For Bardet-Biedl syndrome (Orphanet):

Inheritance: Autosomal recessive, Oligogenic
Onset: Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Specific population)

Similar variants

TTC8 p.His201fs Pathogenic/Likely pathogenic ★★ same condition
TTC8 p.Ala345fs Pathogenic ★ same condition
TTC8 p.Arg110Ter Pathogenic ★ same condition
TTC8 p.Glu197Ter Pathogenic ★ same condition
TTC8 p.Tyr36fs Pathogenic ★ same condition
TTC8 c.1049+2_1049+4del Pathogenic ★★ same condition
TTC8 c.114+2T>C Pathogenic/Likely pathogenic ★★ same condition
TTC8 c.265+1G>A Pathogenic/Likely pathogenic ★★ 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/ttc8-p-ala277fs (accessed [today's date]).

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