Is CHTF18 p.Pro288Leu (c.863C>T) pathogenic?

CHTF18 p.Pro288Leu (c.863C>T) is classified Uncertain significance in CHTF18 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely pathogenic (0.8487); Very rare (popmax 0.0052%, amr).

How common is CHTF18 p.Pro288Leu (c.863C>T) in the general population?

CHTF18 p.Pro288Leu (c.863C>T) is very rare (popmax 0.0052%, amr) (gnomAD).

What do computational predictors say about CHTF18 p.Pro288Leu (c.863C>T)?

AlphaMissense predicts likely pathogenic (score 0.8487) — an in-silico prediction, not a clinical call.

CHTF18 p.Pro288Leu

c.863C>T · VCV4228753

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8487 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0052%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8487	likely pathogenic · top 9% in CHTF18
REVEL	0.578	indeterminate
SaProt	LLR -12.86	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 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 1.43	unconstrained · MANE · 9,287 bp · p 1.1e-58 · regional, not allelic
Overall
CADD	24.7	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 0.0052% Admixed American · 3/57,728 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000682%

Overall 0.000555% 8/1,442,564 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0052%	19,243
African / African-American	0.00134%	74,514
European (non-Finnish)	0.000341%	293,266

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: CHTF18
Protein: p.Pro288Leu
Coding: c.863C>T
MANE Select: NM_022092
Type: single nucleotide variant
Location: chr16:790635 (GRCh38)
Gene constraint: LOEUF 1.712 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.97 · 10 PDB

Full CHTF18 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHTF18 p.Pro288Ala Uncertain significance ★ ⚠ same residue
CHTF18 p.Ala770= Benign ★★ same type
CHTF18 p.Arg804Cys Benign ★★ same type
CHTF18 p.Asn820= Benign ★★ same type
CHTF18 p.Asp284Glu Benign ★★ same type
CHTF18 p.Glu233Lys Benign ★★ same type
CHTF18 p.His179= Benign ★★ same type
CHTF18 p.Leu541= Benign ★★ same type

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/chtf18-p-pro288leu (accessed [today's date]).

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