Is TULP1 p.Pro176fs (c.524dup) pathogenic?

TULP1 p.Pro176fs (c.524dup) is classified Pathogenic in TULP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-11-02). Very rare (popmax 0.0011%, sas); Associated with Leber congenital amaurosis 1.

What condition is associated with TULP1 p.Pro176fs (c.524dup)?

TULP1 p.Pro176fs (c.524dup) is associated with Leber congenital amaurosis 1 (ClinVar).

How common is TULP1 p.Pro176fs (c.524dup) in the general population?

TULP1 p.Pro176fs (c.524dup) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Leber congenital amaurosis inherited?

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

TULP1 p.Pro176fs

c.524dup · rs1327062642 · VCV547179

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Leber congenital amaurosis 1

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 6 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.39	GERP -3.1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,058 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000372% 6/1,613,670 alleles · very rare exomes 6/1,461,712 · genomes 0/151,958 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,492
Finnishnot grpmax-eligible	0.00157%	63,816
South Asiangrpmax	0.0011%	91,058
European (non-Finnish)	0.000254%	393,314

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: TULP1
Protein: p.Pro176fs
Coding: c.524dup
MANE Select: NM_003322
dbSNP: rs1327062642
Type: Duplication
Location: chr6:35509903 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.10 · 2 PDB
Residue 176: the 'disordered' region

Full TULP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Leber congenital amaurosis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Leber congenital amaurosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

TULP1 p.Pro176= Likely benign ★★ same residue
TULP1 p.Pro176Ser Uncertain significance ★ ⚠ same residue
TULP1 p.Arg311Trp Pathogenic/Likely pathogenic ★★ same condition
TULP1 p.Ile259Thr Benign ★★ same condition
TULP1 p.Arg361Gln Conflicting classifications of pathogenicity ★ ⚠ same condition
TULP1 p.Gln301fs Pathogenic/Likely pathogenic ★★ same type
TULP1 p.Thr55fs Pathogenic/Likely pathogenic ★★ same type
TULP1 p.Val286fs Pathogenic/Likely pathogenic ★★ 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/tulp1-p-pro176fs (accessed [today's date]).

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