Is CTBP1 p.Arg331Trp (c.991C>T) pathogenic?

CTBP1 p.Arg331Trp (c.991C>T) is classified Pathogenic in CTBP1 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-03-05). AlphaMissense: ambiguous (0.4961); Absent from gnomAD v4.1; Associated with hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome.

What condition is associated with CTBP1 p.Arg331Trp (c.991C>T)?

CTBP1 p.Arg331Trp (c.991C>T) is associated with hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome (ClinVar).

How common is CTBP1 p.Arg331Trp (c.991C>T) in the general population?

CTBP1 p.Arg331Trp (c.991C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CTBP1 p.Arg331Trp (c.991C>T)?

AlphaMissense predicts ambiguous (score 0.4961) — an in-silico prediction, not a clinical call.

CTBP1 p.Arg331Trp

c.991C>T · rs869320802 · VCV225758

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

AlphaMissense

ambiguous

0.4961 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.4961	ambiguous
REVEL	0.743	pathogenic-leaning
SaProt	LLR -15.55	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.81 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.3	GERP 0.47, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 16 kb · p 2.8e-17 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R342W vs ClinVar R331W) — 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.Arg331Trp
Coding: c.991C>T
MANE Select: NM_001012614
dbSNP: rs869320802
Type: single nucleotide variant
Location: chr4:1213028 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 84.08 · 11 PDB
Residue 331: the 'interaction with glis2 2' region; an α-helix

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.Arg331Gln Uncertain significance ★ ⚠ same residue
CTBP1 p.Arg331= Benign ★ same residue
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

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-arg331trp (accessed [today's date]).

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