Is TULP1 p.Arg400Trp (c.1198C>T) pathogenic?

TULP1 p.Arg400Trp (c.1198C>T) is classified Pathogenic/Likely pathogenic in TULP1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-27). AlphaMissense: likely pathogenic (0.9575); Very rare (popmax 0.0022%, sas); Associated with brachydactyly.

What condition is associated with TULP1 p.Arg400Trp (c.1198C>T)?

TULP1 p.Arg400Trp (c.1198C>T) is associated with brachydactyly, retinal degeneration, polydactyly, postaxial, type A1 (ClinVar).

How common is TULP1 p.Arg400Trp (c.1198C>T) in the general population?

TULP1 p.Arg400Trp (c.1198C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about TULP1 p.Arg400Trp (c.1198C>T)?

AlphaMissense predicts likely pathogenic (score 0.9575) — an in-silico prediction, not a clinical call.

TULP1 p.Arg400Trp

c.1198C>T · rs387906836 · VCV30261

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9575 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

brachydactyly

Computational evidence

Protein change
AlphaMissense	0.9575	likely pathogenic ✓ concordant with ClinVar
REVEL	0.969	strongly pathogenic-leaning
SaProt	LLR -14.93	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.30	donor loss, 26 bp away · masked 0 · deltas
Pangolin	Δ0.27	loss · gain 0.04 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 8.5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 7,948 bp · p 0.64 · regional, not allelic
Overall
CADD	33.0	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 0.0022% South Asian · 2/90,956 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000124% 2/1,613,494 alleles · very rare exomes 2/1,461,180 · genomes 0/152,314 · 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.Arg400Trp
Coding: c.1198C>T
MANE Select: NM_003322
dbSNP: rs387906836
Type: single nucleotide variant
Location: chr6:35503763 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.10 · 2 PDB
Residue 400: a UniProt-annotated variant site (in lca15)

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

Disease context

brachydactyly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinal degeneration polydactyly, postaxial, type A1 Leber congenital amaurosis 15 Leber congenital amaurosis inherited retinal dystrophy syndactyly

Similar variants

TULP1 p.Arg400Gln Pathogenic/Likely pathogenic ★★ same residue
TULP1 p.Arg400Pro Uncertain significance ★ ⚠ 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
TULP1 p.Arg311Trp 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-arg400trp (accessed [today's date]).

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