Is TBC1D2B p.Pro552Ser (c.1654C>T) pathogenic?

TBC1D2B p.Pro552Ser (c.1654C>T) is classified Uncertain significance in TBC1D2B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-11). AlphaMissense: ambiguous (0.5034); Very rare (popmax 0.00269%, afr); Associated with Inborn genetic diseases.

What condition is associated with TBC1D2B p.Pro552Ser (c.1654C>T)?

TBC1D2B p.Pro552Ser (c.1654C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TBC1D2B p.Pro552Ser (c.1654C>T) in the general population?

TBC1D2B p.Pro552Ser (c.1654C>T) is very rare (popmax 0.00269%, afr) (gnomAD).

What do computational predictors say about TBC1D2B p.Pro552Ser (c.1654C>T)?

AlphaMissense predicts ambiguous (score 0.5034) — an in-silico prediction, not a clinical call.

TBC1D2B p.Pro552Ser

c.1654C>T · rs747714125 · VCV2610282

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5034 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00269%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5034	ambiguous
REVEL	0.286	benign-leaning
SaProt	LLR -6.79	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.3, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 16 kb · p 2e-05 · regional, not allelic
Overall
CADD	24.5	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 0.00269% African / African-American · 2/74,426 alleles

Filtering AF 0.000446% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000167%

Overall 0.000124% 2/1,607,718 alleles · very rare exomes 1/1,455,508 · genomes 1/152,210 · 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: TBC1D2B
Protein: p.Pro552Ser
Coding: c.1654C>T
MANE Select: NM_144572
dbSNP: rs747714125
Type: single nucleotide variant
Location: chr15:78016667 (GRCh38)
Gene constraint: LOEUF 0.739 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.68
Residue 552: a UniProt-annotated variant site (in nedsgo; pathogenic)

Full TBC1D2B 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

TBC1D2B p.Pro552Leu Uncertain significance ★ same residue
TBC1D2B p.Tyr66Cys Uncertain significance ★★ ⚠ same condition
TBC1D2B p.Ala121Thr Uncertain significance ★ ⚠ same condition
TBC1D2B p.Ala203Val Uncertain significance ★ ⚠ same condition
TBC1D2B p.Ala28Pro Uncertain significance ★ ⚠ same condition
TBC1D2B p.Ala35Val Uncertain significance ★ ⚠ same condition
TBC1D2B p.Ala661Val Uncertain significance ★ ⚠ same condition
TBC1D2B p.Ala699Val 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/tbc1d2b-p-pro552ser (accessed [today's date]).

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