Is TBC1D1 p.His599Pro (c.1796A>C) pathogenic?

TBC1D1 p.His599Pro (c.1796A>C) is classified Uncertain significance in TBC1D1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-25). AlphaMissense: likely benign (0.174); Very rare (popmax 0.00212%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TBC1D1 p.His599Pro (c.1796A>C)?

TBC1D1 p.His599Pro (c.1796A>C) is associated with Inborn genetic diseases (ClinVar).

How common is TBC1D1 p.His599Pro (c.1796A>C) in the general population?

TBC1D1 p.His599Pro (c.1796A>C) is very rare (popmax 0.00212%, nfe) (gnomAD).

What do computational predictors say about TBC1D1 p.His599Pro (c.1796A>C)?

AlphaMissense predicts likely benign (score 0.174) — an in-silico prediction, not a clinical call.

TBC1D1 p.His599Pro

c.1796A>C · rs1036215727 · VCV2392914

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.174 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.174	likely benign
REVEL	0.352	indeterminate
SaProt	LLR -6.72	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Overall
CADD	25.1	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 0.00212% European (non-Finnish) · 25/1,179,982 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00155% 25/1,614,070 alleles · very rare exomes 25/1,461,892 · genomes 0/152,178 · 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: TBC1D1
Protein: p.His599Pro
Coding: c.1796A>C
MANE Select: NM_001396959
dbSNP: rs1036215727
Type: single nucleotide variant
Location: chr4:38049784 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.31 · 1 PDB

Full TBC1D1 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

Similar variants

TBC1D1 p.Arg897His Uncertain significance ★★ ⚠ same condition
TBC1D1 p.Asn201Ser Uncertain significance ★★ ⚠ same condition
TBC1D1 p.His124Tyr Uncertain significance ★★ ⚠ same condition
TBC1D1 p.Ala1003Thr Uncertain significance ★ ⚠ same condition
TBC1D1 p.Ala1245Thr Uncertain significance ★ ⚠ same condition
TBC1D1 p.Ala375Ser Uncertain significance ★ ⚠ same condition
TBC1D1 p.Ala500Glu Uncertain significance ★ ⚠ same condition
TBC1D1 p.Ala552Asp 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/tbc1d1-p-his599pro (accessed [today's date]).

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