Is TULP1 p.Gln85Arg (c.254A>G) pathogenic?

TULP1 p.Gln85Arg (c.254A>G) is classified Uncertain significance in TULP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-10-20). AlphaMissense: likely benign (0.0661); Ultra-rare (popmax 0.0159%, amr); Associated with Leber congenital amaurosis 15.

What condition is associated with TULP1 p.Gln85Arg (c.254A>G)?

TULP1 p.Gln85Arg (c.254A>G) is associated with Leber congenital amaurosis 15, retinitis pigmentosa (ClinVar).

How common is TULP1 p.Gln85Arg (c.254A>G) in the general population?

TULP1 p.Gln85Arg (c.254A>G) is ultra-rare (popmax 0.0159%, amr) (gnomAD).

How is Leber congenital amaurosis 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.Gln85Arg (c.254A>G)?

AlphaMissense predicts likely benign (score 0.0661) — an in-silico prediction, not a clinical call.

TULP1 p.Gln85Arg

c.254A>G · rs754040672 · VCV356473

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0661 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0159%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Leber congenital amaurosis 15

Computational evidence

Protein change
AlphaMissense	0.0661	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -4.73	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 -2.1	GERP -2.5
Regional constraint	o/e 1.05	unconstrained · MANE · 3,598 bp · p 0.36 · regional, not allelic
Overall
CADD	4.435	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 0.0159% Admixed American · 9/56,644 alleles

Filtering AF 0.00825% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00619%

Overall 0.000693% 11/1,586,674 alleles · ultra-rare exomes 10/1,434,650 · genomes 1/152,024 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0159%	6,294
South Asian	0.0023%	43,493

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.Gln85Arg
Coding: c.254A>G
MANE Select: NM_003322
dbSNP: rs754040672
Type: single nucleotide variant
Location: chr6:35511743 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.10 · 2 PDB
Residue 85: the 'disordered' region

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

Disease context

Leber congenital amaurosis 15 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa

For Leber congenital amaurosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (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.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
TULP1 p.Arg400Gln 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-gln85arg (accessed [today's date]).

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