Is TULP1 p.Arg416Cys (c.1246C>T) pathogenic?

TULP1 p.Arg416Cys (c.1246C>T) is classified Conflicting classifications of pathogenicity in TULP1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-06-23). AlphaMissense: likely pathogenic (0.7006); Ultra-rare (popmax 0.0165%, mid); Associated with inherited retinal dystrophy.

What condition is associated with TULP1 p.Arg416Cys (c.1246C>T)?

TULP1 p.Arg416Cys (c.1246C>T) is associated with inherited retinal dystrophy, retinitis pigmentosa 14 (ClinVar).

How common is TULP1 p.Arg416Cys (c.1246C>T) in the general population?

TULP1 p.Arg416Cys (c.1246C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about TULP1 p.Arg416Cys (c.1246C>T)?

AlphaMissense predicts likely pathogenic (score 0.7006) — an in-silico prediction, not a clinical call.

TULP1 p.Arg416Cys

c.1246C>T · rs200769197 · VCV1683297

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.7006 · 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	0.7006	likely pathogenic
REVEL	0.945	strongly pathogenic-leaning
SaProt	LLR -12.12	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 6.6	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 · 1/6,048 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00075% 12/1,599,866 alleles · ultra-rare exomes 11/1,447,526 · genomes 1/152,340 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,048
East Asian	0.0068%	14,697
South Asian	0.00226%	44,204
European (non-Finnish)	0.000511%	195,575

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.Arg416Cys
Coding: c.1246C>T
MANE Select: NM_003322
dbSNP: rs200769197
Type: single nucleotide variant
Location: chr6:35503636 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.10 · 2 PDB
Residue 416: a β-strand

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

Similar variants

TULP1 p.Arg416His Uncertain significance ★★ same residue
TULP1 p.Arg416= Likely benign ★★ same residue
TULP1 p.Arg416Leu Likely pathogenic ★ 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-arg416cys (accessed [today's date]).

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