Is CTH p.Ala146Pro (c.436G>C) pathogenic?

CTH p.Ala146Pro (c.436G>C) is classified Uncertain significance in CTH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-08). AlphaMissense: likely pathogenic (0.8933); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CTH p.Ala146Pro (c.436G>C)?

CTH p.Ala146Pro (c.436G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CTH p.Ala146Pro (c.436G>C) in the general population?

CTH p.Ala146Pro (c.436G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CTH p.Ala146Pro (c.436G>C)?

AlphaMissense predicts likely pathogenic (score 0.8933) — an in-silico prediction, not a clinical call.

CTH p.Ala146Pro

c.436G>C · VCV3498169

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8933 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8933	likely pathogenic · top 7% in CTH
REVEL	0.887	moderately pathogenic-leaning
SaProt	LLR -14.21	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 12	GERP 1.7, phastCons 1
Overall
CADD	26.5	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

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: CTH
Protein: p.Ala146Pro
Coding: c.436G>C
MANE Select: NM_014312 · reported on NM_001902
Type: single nucleotide variant
Location: chr1:70421655 (GRCh38)
Structure: AlphaFold pLDDT 80.30
Residue 146: the ig-like c2-type domain

Full CTH 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

CTH p.Asp181Asn Uncertain significance ★★ ⚠ same condition
CTH p.Thr158Ile Uncertain significance ★★ ⚠ same condition
CTH p.Ala103Ser Uncertain significance ★ ⚠ same condition
CTH p.Ala245Thr Uncertain significance ★ ⚠ same condition
CTH p.Ala51Thr Uncertain significance ★ ⚠ same condition
CTH p.Ala6Thr Uncertain significance ★ ⚠ same condition
CTH p.Arg62Pro Uncertain significance ★ ⚠ same condition
CTH p.Asn234Asp 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/cth-p-ala146pro (accessed [today's date]).

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