Is TBC1D23 p.Ser375Pro (c.1123T>C) pathogenic?

TBC1D23 p.Ser375Pro (c.1123T>C) is classified Uncertain significance in TBC1D23 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-23). AlphaMissense: likely pathogenic (0.9977); Very rare (popmax 0.00297%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TBC1D23 p.Ser375Pro (c.1123T>C)?

TBC1D23 p.Ser375Pro (c.1123T>C) is associated with Inborn genetic diseases (ClinVar).

How common is TBC1D23 p.Ser375Pro (c.1123T>C) in the general population?

TBC1D23 p.Ser375Pro (c.1123T>C) is very rare (popmax 0.00297%, nfe) (gnomAD).

What do computational predictors say about TBC1D23 p.Ser375Pro (c.1123T>C)?

AlphaMissense predicts likely pathogenic (score 0.9977) — an in-silico prediction, not a clinical call.

TBC1D23 p.Ser375Pro

c.1123T>C · VCV4180775

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00297%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9977	likely pathogenic · top 4% in TBC1D23
REVEL	0.427	indeterminate
SaProt	LLR -15.84	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 63 kb · p 0.00012 · regional, not allelic
Overall
CADD	28.5	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

Grpmax group 0.00297% European (non-Finnish) · 35/1,179,820 alleles

Filtering AF 0.00215% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00191%

Overall 0.00217% 35/1,613,412 alleles · very rare

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: TBC1D23
Protein: p.Ser375Pro
Coding: c.1123T>C
MANE Select: NM_001199198
Type: single nucleotide variant
Location: chr3:100302097 (GRCh38)
Gene constraint: LOEUF 0.882 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.69 · 4 PDB
Residue 375: the rhodanese domain; an α-helix

Full TBC1D23 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

TBC1D23 p.Asn154Asp Uncertain significance ★★ ⚠ same condition
TBC1D23 p.Ile429Thr Uncertain significance ★★ ⚠ same condition
TBC1D23 c.2019-5C>T Uncertain significance ★ same condition
TBC1D23 c.272-5T>C Uncertain significance ★ same condition
TBC1D23 p.Ala100Thr Uncertain significance ★ ⚠ same condition
TBC1D23 p.Ala241Pro Uncertain significance ★ ⚠ same condition
TBC1D23 p.Ala328Val Uncertain significance ★ ⚠ same condition
TBC1D23 p.Ala670Ser 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/tbc1d23-p-ser375pro (accessed [today's date]).

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