Is TULP1 p.Phe506Leu (c.1518C>A) pathogenic?

TULP1 p.Phe506Leu (c.1518C>A) is classified Conflicting classifications of pathogenicity in TULP1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-12-19). AlphaMissense: likely pathogenic (0.9982); Very rare (popmax 6.2e-05%); Associated with Leber congenital amaurosis 15.

What condition is associated with TULP1 p.Phe506Leu (c.1518C>A)?

TULP1 p.Phe506Leu (c.1518C>A) is associated with Leber congenital amaurosis 15 (ClinVar).

How common is TULP1 p.Phe506Leu (c.1518C>A) in the general population?

TULP1 p.Phe506Leu (c.1518C>A) is very rare (popmax 6.2e-05%) (gnomAD).

How is Leber congenital amaurosis inherited?

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

What do computational predictors say about TULP1 p.Phe506Leu (c.1518C>A)?

AlphaMissense predicts likely pathogenic (score 0.9982) — an in-silico prediction, not a clinical call.

TULP1 p.Phe506Leu

c.1518C>A · rs764536885 · VCV2438445

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9982 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Leber congenital amaurosis 15

Computational evidence

Protein change
AlphaMissense	0.9982	likely pathogenic · top 1% in TULP1
REVEL	0.744	pathogenic-leaning
SaProt	LLR -12.50	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.67	GERP -4.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 7,948 bp · p 0.64 · regional, not allelic
Overall
CADD	21.1	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 6.2e-05%

Overall 6.2e-05% 1/1,613,966 alleles · very rare exomes 1/1,461,604 · genomes 0/152,362 · 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: TULP1
Protein: p.Phe506Leu
Coding: c.1518C>A
MANE Select: NM_003322
dbSNP: rs764536885
Type: single nucleotide variant
Location: chr6:35498438 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.10 · 2 PDB
Residue 506: a β-strand

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

Disease context

Leber congenital amaurosis 15 — 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.Phe506= Likely benign ★★ same residue
TULP1 c.1495+1G>A Pathogenic/Likely pathogenic ★★ same condition
TULP1 c.1496-6C>A Pathogenic/Likely pathogenic ★★ same condition
TULP1 c.99+1G>A Pathogenic/Likely pathogenic ★★ same condition
TULP1 p.Arg311Gln Pathogenic/Likely pathogenic ★★ same condition
TULP1 p.Arg311Trp Pathogenic/Likely pathogenic ★★ same condition
TULP1 p.Arg342Ter Pathogenic/Likely pathogenic ★★ same condition
TULP1 p.Arg34Ter 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/tulp1-p-phe506leu (accessed [today's date]).

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