Is CHTF18 p.Arg966Trp (c.2896C>T) pathogenic?

CHTF18 p.Arg966Trp (c.2896C>T) is classified Uncertain significance in CHTF18 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-18). AlphaMissense: likely pathogenic (0.7607); Ultra-rare (popmax 0.0183%, amr).

How common is CHTF18 p.Arg966Trp (c.2896C>T) in the general population?

CHTF18 p.Arg966Trp (c.2896C>T) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

What do computational predictors say about CHTF18 p.Arg966Trp (c.2896C>T)?

AlphaMissense predicts likely pathogenic (score 0.7607) — an in-silico prediction, not a clinical call.

CHTF18 p.Arg966Trp

c.2896C>T · VCV3267277

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7607 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7607	likely pathogenic
REVEL	0.605	indeterminate
SaProt	LLR -9.64	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -0.052, phastCons 1
Regional constraint	o/e 1.43	unconstrained · MANE · 9,287 bp · p 1.1e-58 · regional, not allelic
Overall
CADD	23.6	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 0.0183% Admixed American · 11/59,978 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00811%

Overall 0.00639% 103/1,612,272 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,453
African / African-American	0.0173%	5,773
East Asian	0.0134%	7,480
European (non-Finnish)	0.00568%	17,608
Remaining individualsnot grpmax-eligible	0.0048%	20,819
South Asian	0.0033%	30,337

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.Arg966Trp
Coding: c.2896C>T
MANE Select: NM_022092
Type: single nucleotide variant
Location: chr16:797943 (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.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-arg966trp (accessed [today's date]).

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