Is TULP1 p.Arg449Cys (c.1345C>T) pathogenic?

TULP1 p.Arg449Cys (c.1345C>T) is classified Uncertain significance in TULP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-03-29). AlphaMissense: likely pathogenic (0.5971); Very rare (popmax 0.0022%, sas); Associated with Inborn genetic diseases.

What condition is associated with TULP1 p.Arg449Cys (c.1345C>T)?

TULP1 p.Arg449Cys (c.1345C>T) is associated with Inborn genetic diseases, retinitis pigmentosa (ClinVar).

How common is TULP1 p.Arg449Cys (c.1345C>T) in the general population?

TULP1 p.Arg449Cys (c.1345C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about TULP1 p.Arg449Cys (c.1345C>T)?

AlphaMissense predicts likely pathogenic (score 0.5971) — an in-silico prediction, not a clinical call.

TULP1 p.Arg449Cys

c.1345C>T · rs1480273410 · VCV973373

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5971 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5971	likely pathogenic
REVEL	0.803	moderately pathogenic-leaning
SaProt	LLR -12.66	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.20	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 7,948 bp · p 0.64 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0022% South Asian · 2/91,090 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000434% 7/1,613,988 alleles · very rare exomes 5/1,461,798 · genomes 2/152,190 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,545
Remaining individualsnot grpmax-eligible	0.0016%	62,490
African / African-American	0.00134%	74,898
European (non-Finnish)	0.000254%	393,346

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.Arg449Cys
Coding: c.1345C>T
MANE Select: NM_003322
dbSNP: rs1480273410
Type: single nucleotide variant
Location: chr6:35500131 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.10 · 2 PDB
Residue 449: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa

Similar variants

TULP1 p.Arg449His Uncertain significance ★ ⚠ same residue
TULP1 c.1496-6C>A Pathogenic/Likely pathogenic ★★ same condition
TULP1 p.Asn349Lys Pathogenic/Likely pathogenic ★★ same condition
TULP1 p.Gln163Ter Pathogenic ★★ same condition
TULP1 p.Gln80Ter Pathogenic ★★ same condition
TULP1 p.Phe382Ser Pathogenic ★★ same condition
TULP1 p.Val423Ala Pathogenic/Likely pathogenic ★★ same condition
TULP1 c.1495+3G>A Uncertain significance ★★ 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-arg449cys (accessed [today's date]).

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