Is TULP1 p.Lys99Arg (c.296A>G) pathogenic?

TULP1 p.Lys99Arg (c.296A>G) is classified Uncertain significance in TULP1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-12). AlphaMissense: likely benign (0.0874); Ultra-rare (popmax 0.0176%, nfe); Associated with retinitis pigmentosa.

What condition is associated with TULP1 p.Lys99Arg (c.296A>G)?

TULP1 p.Lys99Arg (c.296A>G) is associated with retinitis pigmentosa, Leber congenital amaurosis 15, inherited retinal dystrophy (ClinVar).

How common is TULP1 p.Lys99Arg (c.296A>G) in the general population?

TULP1 p.Lys99Arg (c.296A>G) is ultra-rare (popmax 0.0176%, nfe) (gnomAD).

How is Retinitis pigmentosa 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.Lys99Arg (c.296A>G)?

AlphaMissense predicts likely benign (score 0.0874) — an in-silico prediction, not a clinical call.

TULP1 p.Lys99Arg

c.296A>G · rs145518705 · VCV844244

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0874 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

retinitis pigmentosa

Computational evidence

Protein change
AlphaMissense	0.0874	likely benign
REVEL	0.31	indeterminate
SaProt	LLR -5.41	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.2	GERP 1.5, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 3,598 bp · p 0.36 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0176% European (non-Finnish) · 206/1,170,330 alleles

Filtering AF 0.0156% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0148%

Overall 0.0135% 215/1,593,980 alleles · ultra-rare exomes 205/1,441,966 · genomes 10/152,014 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0176%	5,681
Remaining individualsnot grpmax-eligible	0.00974%	10,272
Finnishnot grpmax-eligible	0.00323%	30,994
South Asian	0.00114%	87,578

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.Lys99Arg
Coding: c.296A>G
MANE Select: NM_003322
dbSNP: rs145518705
Type: single nucleotide variant
Location: chr6:35511701 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.10 · 2 PDB
Residue 99: the 'disordered' region

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

Disease context

retinitis pigmentosa — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Leber congenital amaurosis 15 inherited retinal dystrophy

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

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 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-lys99arg (accessed [today's date]).

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