Is TULP1 p.Lys489Arg (c.1466A>G) pathogenic?

TULP1 p.Lys489Arg (c.1466A>G) is classified Pathogenic/Likely pathogenic in TULP1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2024-06-14). AlphaMissense: likely pathogenic (0.9134); Ultra-rare (popmax 0.0263%, sas); Associated with TULP1-related disorder.

What condition is associated with TULP1 p.Lys489Arg (c.1466A>G)?

TULP1 p.Lys489Arg (c.1466A>G) is associated with TULP1-related disorder, retinitis pigmentosa 14, Leber congenital amaurosis 15 (ClinVar).

How common is TULP1 p.Lys489Arg (c.1466A>G) in the general population?

TULP1 p.Lys489Arg (c.1466A>G) is ultra-rare (popmax 0.0263%, sas) (gnomAD).

What do computational predictors say about TULP1 p.Lys489Arg (c.1466A>G)?

AlphaMissense predicts likely pathogenic (score 0.9134) — an in-silico prediction, not a clinical call.

TULP1 p.Lys489Arg

c.1466A>G · rs62636511 · VCV99663

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9134 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0263%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TULP1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9134	likely pathogenic ✓ concordant with ClinVar
REVEL	0.94	strongly pathogenic-leaning
SaProt	LLR -11.91	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 6.1	GERP 2.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 7,948 bp · p 0.64 · regional, not allelic
Overall
CADD	27.9	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 0.0263% South Asian · 24/91,084 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.00155% 25/1,614,116 alleles · ultra-rare exomes 25/1,461,858 · genomes 0/152,258 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0263%	3,795
European (non-Finnish)	8.47e-05%	1,180,011

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.Lys489Arg
Coding: c.1466A>G
MANE Select: NM_003322
dbSNP: rs62636511
Type: single nucleotide variant
Location: chr6:35500010 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.10 · 2 PDB
Residue 489: a UniProt-annotated variant site (in rp14; abolishes rpe phagocytosis)

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

Disease context

TULP1-related disorder

Also linked: retinitis pigmentosa 14 Leber congenital amaurosis 15 Leber congenital amaurosis inherited retinal dystrophy

Similar variants

TULP1 c.1112+1G>A Likely pathogenic ★★ same condition
TULP1 c.1495+1G>A Pathogenic/Likely pathogenic ★★ same condition
TULP1 c.1496-6C>A Pathogenic/Likely pathogenic ★★ same condition
TULP1 c.718+2T>C Pathogenic ★★ same condition
TULP1 c.99+1G>A Pathogenic/Likely pathogenic ★★ same condition
TULP1 c.999+5G>C Pathogenic/Likely pathogenic ★★ same condition
TULP1 p.Arg311Gln Pathogenic/Likely pathogenic ★★ same condition
TULP1 p.Arg311Trp 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-lys489arg (accessed [today's date]).

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