Is CHTF18 p.Leu708Pro (c.2123T>C) pathogenic?

CHTF18 p.Leu708Pro (c.2123T>C) is classified Uncertain significance in CHTF18 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-29). AlphaMissense: likely pathogenic (0.736); Ultra-rare (popmax 0.0432%, amr).

How common is CHTF18 p.Leu708Pro (c.2123T>C) in the general population?

CHTF18 p.Leu708Pro (c.2123T>C) is ultra-rare (popmax 0.0432%, amr) (gnomAD).

What do computational predictors say about CHTF18 p.Leu708Pro (c.2123T>C)?

AlphaMissense predicts likely pathogenic (score 0.736) — an in-silico prediction, not a clinical call.

CHTF18 p.Leu708Pro

c.2123T>C · VCV4002853

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.736 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0432%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.736	likely pathogenic
REVEL	0.607	indeterminate
SaProt	LLR -14.15	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 2.1, phastCons 1
Regional constraint	o/e 1.43	unconstrained · MANE · 9,287 bp · p 1.1e-58 · regional, not allelic
Overall
CADD	24.0	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 0.0432% Admixed American · 22/50,964 alleles

Filtering AF 0.0291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0246%

Overall 0.00168% 26/1,548,510 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0432%	2,317
European (non-Finnish)	0.000349%	286,656

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.Leu708Pro
Coding: c.2123T>C
MANE Select: NM_022092
Type: single nucleotide variant
Location: chr16:795304 (GRCh38)
Gene constraint: LOEUF 1.712 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.97 · 10 PDB
Residue 708: 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-leu708pro (accessed [today's date]).

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