Is TULP1 p.Arg419Gln (c.1256G>A) pathogenic?

TULP1 p.Arg419Gln (c.1256G>A) is classified Conflicting classifications of pathogenicity in TULP1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-03-31). AlphaMissense: likely pathogenic (0.9825); Ultra-rare (popmax 0.0165%, mid); Associated with inherited retinal dystrophy.

What condition is associated with TULP1 p.Arg419Gln (c.1256G>A)?

TULP1 p.Arg419Gln (c.1256G>A) is associated with inherited retinal dystrophy, retinitis pigmentosa 14, Leber congenital amaurosis 15 (ClinVar).

How common is TULP1 p.Arg419Gln (c.1256G>A) in the general population?

TULP1 p.Arg419Gln (c.1256G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about TULP1 p.Arg419Gln (c.1256G>A)?

AlphaMissense predicts likely pathogenic (score 0.9825) — an in-silico prediction, not a clinical call.

TULP1 p.Arg419Gln

c.1256G>A · rs770045008 · VCV191207

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9825 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.9825	likely pathogenic · top 9% in TULP1
REVEL	0.962	strongly pathogenic-leaning
SaProt	LLR -13.00	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 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 7,948 bp · p 0.64 · regional, not allelic
Overall
CADD	32.0	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 0.0165% Middle Eastern · 1/6,070 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000938% 15/1,599,184 alleles · ultra-rare exomes 12/1,446,982 · genomes 3/152,202 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,070
African / African-American	0.00536%	18,648
South Asian	0.00113%	88,318
European (non-Finnish)	0.000767%	130,353

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.Arg419Gln
Coding: c.1256G>A
MANE Select: NM_003322
dbSNP: rs770045008
Type: single nucleotide variant
Location: chr6:35503626 (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

Also linked: retinitis pigmentosa 14 Leber congenital amaurosis 15 Leber congenital amaurosis

Similar variants

TULP1 p.Arg419Trp Pathogenic/Likely pathogenic ★★ same residue
TULP1 p.Arg419fs Pathogenic/Likely pathogenic ★★ same residue
TULP1 p.Arg419= 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.718+2T>C Pathogenic ★★ same condition
TULP1 c.99+1G>A Pathogenic/Likely pathogenic ★★ same condition
TULP1 p.Arg311Gln 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-arg419gln (accessed [today's date]).

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