Is TULP1 p.Pro521Ser (c.1561C>T) pathogenic?

TULP1 p.Pro521Ser (c.1561C>T) is classified Likely pathogenic in TULP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-27). AlphaMissense: likely pathogenic (0.9958); Very rare (popmax 0.0011%, sas); Associated with inherited retinal dystrophy.

What condition is associated with TULP1 p.Pro521Ser (c.1561C>T)?

TULP1 p.Pro521Ser (c.1561C>T) is associated with inherited retinal dystrophy (ClinVar).

How common is TULP1 p.Pro521Ser (c.1561C>T) in the general population?

TULP1 p.Pro521Ser (c.1561C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about TULP1 p.Pro521Ser (c.1561C>T)?

AlphaMissense predicts likely pathogenic (score 0.9958) — an in-silico prediction, not a clinical call.

TULP1 p.Pro521Ser

c.1561C>T · VCV3381777

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9958 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.9958	likely pathogenic ✓ concordant with ClinVar · top 4% in TULP1
REVEL	0.968	strongly pathogenic-leaning
SaProt	LLR -14.11	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 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 7,948 bp · p 0.64 · regional, not allelic
Overall
CADD	33.0	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 0.0011% South Asian · 1/91,076 alleles

Overall 0.000124% 2/1,613,916 alleles · very rare exomes 2/1,461,562 · genomes 0/152,354 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,498
South Asiangrpmax	0.0011%	91,076

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.Pro521Ser
Coding: c.1561C>T
MANE Select: NM_003322
Type: single nucleotide variant
Location: chr6:35498395 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.10 · 2 PDB

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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TULP1 p.Pro521Leu Likely pathogenic ★ same residue
TULP1 p.Pro521Thr Pathogenic ★ same residue
TULP1 p.Pro521= Conflicting classifications of pathogenicity ★ same residue
TULP1 c.1496-6C>A Pathogenic/Likely pathogenic ★★ same condition
TULP1 c.718+2T>C Pathogenic ★★ same condition
TULP1 p.Arg361Ter Pathogenic ★★ same condition
TULP1 p.Arg400Trp Pathogenic/Likely pathogenic ★★ same condition
TULP1 p.Arg419Trp 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/tulp1-p-pro521ser (accessed [today's date]).

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