Is TULP1 p.Arg246Ser (c.738G>T) pathogenic?

TULP1 p.Arg246Ser (c.738G>T) is classified Uncertain significance in TULP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-01). AlphaMissense: likely benign (0.1269); Ultra-rare (popmax 0.0201%, eas); Associated with inherited retinal dystrophy.

What condition is associated with TULP1 p.Arg246Ser (c.738G>T)?

TULP1 p.Arg246Ser (c.738G>T) is associated with inherited retinal dystrophy (ClinVar).

How common is TULP1 p.Arg246Ser (c.738G>T) in the general population?

TULP1 p.Arg246Ser (c.738G>T) is ultra-rare (popmax 0.0201%, eas) (gnomAD).

What do computational predictors say about TULP1 p.Arg246Ser (c.738G>T)?

AlphaMissense predicts likely benign (score 0.1269) — an in-silico prediction, not a clinical call.

TULP1 p.Arg246Ser

c.738G>T · rs752126260 · VCV953872

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1269 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.1269	likely benign
REVEL	0.211	benign-leaning
SaProt	LLR -6.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.12	GERP -3.5
Regional constraint	o/e 1.05	unconstrained · MANE · 3,598 bp · p 0.36 · regional, not allelic
Overall
CADD	15.3	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 0.0201% East Asian · 9/44,864 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00779%

Overall 0.000558% 9/1,614,090 alleles · ultra-rare exomes 9/1,461,826 · genomes 0/152,264 · joint denominator

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.Arg246Ser
Coding: c.738G>T
MANE Select: NM_003322
dbSNP: rs752126260
Type: single nucleotide variant
Location: chr6:35509293 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.10 · 2 PDB
Residue 246: the 'disordered' region

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

Similar variants

TULP1 c.1496-6C>A Pathogenic/Likely pathogenic ★★ same condition
TULP1 c.718+2T>C Pathogenic ★★ same condition
TULP1 p.Arg361Ter Pathogenic ★★ same condition
TULP1 p.Arg400Trp Pathogenic/Likely pathogenic ★★ same condition
TULP1 p.Arg419Trp Pathogenic/Likely pathogenic ★★ same condition
TULP1 p.Arg440Ter Pathogenic ★★ same condition
TULP1 p.Asn349Lys Pathogenic/Likely pathogenic ★★ same condition
TULP1 p.Gln401Ter 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-arg246ser (accessed [today's date]).

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