Is CTBP1 p.Leu166Phe (c.498G>C) pathogenic?

CTBP1 p.Leu166Phe (c.498G>C) is classified Uncertain significance in CTBP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-03). AlphaMissense: likely pathogenic (0.8603); Absent from gnomAD v4.1; Associated with hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome.

What condition is associated with CTBP1 p.Leu166Phe (c.498G>C)?

CTBP1 p.Leu166Phe (c.498G>C) is associated with hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (ClinVar).

How common is CTBP1 p.Leu166Phe (c.498G>C) in the general population?

CTBP1 p.Leu166Phe (c.498G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CTBP1 p.Leu166Phe (c.498G>C)?

AlphaMissense predicts likely pathogenic (score 0.8603) — an in-silico prediction, not a clinical call.

CTBP1 p.Leu166Phe

c.498G>C · VCV4855858

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8603 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome

Computational evidence

Protein change
AlphaMissense	0.8603	likely pathogenic
REVEL	0.744	pathogenic-leaning
SaProt	LLR -14.74	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 16 kb · p 2.8e-17 · regional, not allelic
Overall
CADD	27.0	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L177F vs ClinVar L166F) — verify the residue.

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: CTBP1
Protein: p.Leu166Phe
Coding: c.498G>C
MANE Select: NM_001012614
Type: single nucleotide variant
Location: chr4:1225376 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 84.08 · 11 PDB
Residue 166: a turn

Full CTBP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CTBP1 p.Arg331Trp Pathogenic ★★ ⚠ same condition
CTBP1 p.Arg173Cys Uncertain significance ★★ ⚠ same condition
CTBP1 p.Gln137His Uncertain significance ★★ ⚠ same condition
CTBP1 p.Gly399Ser Uncertain significance ★★ ⚠ same condition
CTBP1 p.Val359Met Uncertain significance ★★ ⚠ same condition
CTBP1 p.Val416Ile Uncertain significance ★★ ⚠ same condition
CTBP1 p.Arg162= Benign/Likely benign ★★ same condition
CTBP1 p.Ala112= 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/ctbp1-p-leu166phe (accessed [today's date]).

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