Is CTH p.Pro399Ala (c.1195C>G) pathogenic?

CTH p.Pro399Ala (c.1195C>G) is classified Uncertain significance in CTH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-21). AlphaMissense: likely benign (0.0675); Very rare (popmax 0.00401%, afr); Associated with Inborn genetic diseases.

What condition is associated with CTH p.Pro399Ala (c.1195C>G)?

CTH p.Pro399Ala (c.1195C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CTH p.Pro399Ala (c.1195C>G) in the general population?

CTH p.Pro399Ala (c.1195C>G) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about CTH p.Pro399Ala (c.1195C>G)?

AlphaMissense predicts likely benign (score 0.0675) — an in-silico prediction, not a clinical call.

CTH p.Pro399Ala

c.1195C>G · rs1684664618 · VCV2284525

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0675 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0675	likely benign
REVEL	0.119	moderately benign-leaning
SaProt	LLR -7.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1	GERP -2.1
Overall
CADD	13.98	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00401% African / African-American · 3/74,836 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,611,910 alleles · very rare exomes 0/1,459,928 · genomes 3/151,982 · 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: CTH
Protein: p.Pro399Ala
Coding: c.1195C>G
MANE Select: NM_001902
dbSNP: rs1684664618
Type: single nucleotide variant
Location: chr1:70439104 (GRCh38)
Structure: AlphaFold pLDDT 80.30

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.Ala146Pro 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

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-pro399ala (accessed [today's date]).

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