Is CHTF18 p.Pro720Ser (c.2158C>T) pathogenic?

CHTF18 p.Pro720Ser (c.2158C>T) is classified Uncertain significance in CHTF18 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-04). AlphaMissense: likely pathogenic (0.7162); Ultra-rare (popmax 0.0569%, amr).

How common is CHTF18 p.Pro720Ser (c.2158C>T) in the general population?

CHTF18 p.Pro720Ser (c.2158C>T) is ultra-rare (popmax 0.0569%, amr) (gnomAD).

What do computational predictors say about CHTF18 p.Pro720Ser (c.2158C>T)?

AlphaMissense predicts likely pathogenic (score 0.7162) — an in-silico prediction, not a clinical call.

CHTF18 p.Pro720Ser

c.2158C>T · VCV3492803

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7162 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0569%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7162	likely pathogenic
REVEL	0.278	benign-leaning
SaProt	LLR -12.13	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.72, phastCons 1
Regional constraint	o/e 1.43	unconstrained · MANE · 9,287 bp · p 1.1e-58 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0569% Admixed American · 29/50,944 alleles

Filtering AF 0.0407% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0352%

Overall 0.00278% 43/1,547,762 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0569%	1,757
Remaining individualsnot grpmax-eligible	0.0117%	8,554
Ashkenazi Jewishnot grpmax-eligible	0.0035%	28,592
Finnishnot grpmax-eligible	0.00171%	58,632
European (non-Finnish)	0.000436%	229,308

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.Pro720Ser
Coding: c.2158C>T
MANE Select: NM_022092
Type: single nucleotide variant
Location: chr16:795339 (GRCh38)
Gene constraint: LOEUF 1.712 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.97 · 10 PDB
Residue 720: an α-helix

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

Similar variants

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
CHTF18 p.Leu797= 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-pro720ser (accessed [today's date]).

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