Is TULP3 p.Leu235Pro (c.704T>C) pathogenic?

TULP3 p.Leu235Pro (c.704T>C) is classified Uncertain significance in TULP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-25). AlphaMissense: likely pathogenic (0.9907); Absent from gnomAD v4.1; Associated with hepatorenocardiac degenerative fibrosis.

What condition is associated with TULP3 p.Leu235Pro (c.704T>C)?

TULP3 p.Leu235Pro (c.704T>C) is associated with hepatorenocardiac degenerative fibrosis (ClinVar).

How common is TULP3 p.Leu235Pro (c.704T>C) in the general population?

TULP3 p.Leu235Pro (c.704T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TULP3 p.Leu235Pro (c.704T>C)?

AlphaMissense predicts likely pathogenic (score 0.9907) — an in-silico prediction, not a clinical call.

TULP3 p.Leu235Pro

c.704T>C · VCV4293950

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9907 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hepatorenocardiac degenerative fibrosis

Computational evidence

Protein change
AlphaMissense	0.9907	likely pathogenic · top 6% in TULP3
REVEL	0.99	strongly pathogenic-leaning
SaProt	LLR -17.80	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.1	GERP 0.63, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 48 kb · p 0.45 · regional, not allelic
Overall
CADD	31.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TULP3
Protein: p.Leu235Pro
Coding: c.704T>C
MANE Select: NM_003324
Type: single nucleotide variant
Location: chr12:2933425 (GRCh38)
Gene constraint: LOEUF 1.059 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.51 · 1 PDB
Residue 235: a UniProt-annotated variant site (in hrcdf)

Full TULP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hepatorenocardiac degenerative fibrosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TULP3 p.Leu235Phe Uncertain significance ★ ⚠ same residue
TULP3 c.492+1G>A Likely pathogenic ★ same condition
TULP3 c.809+2T>C Pathogenic ★ same condition
TULP3 c.810-1G>C Likely pathogenic ★ same condition
TULP3 p.Arg382Gln Uncertain significance ★ ⚠ same condition
TULP3 p.Cys204Trp Conflicting classifications of pathogenicity ★ ⚠ same condition
TULP3 c.1023+1G>A Pathogenic same condition
TULP3 p.Arg24Ter 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/tulp3-p-leu235pro (accessed [today's date]).

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