Is CHTF18 p.Leu541Phe (c.1621C>T) pathogenic?

CHTF18 p.Leu541Phe (c.1621C>T) is classified Uncertain significance in CHTF18 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-15). AlphaMissense: ambiguous (0.5099); Ultra-rare (popmax 0.0292%, nfe).

How common is CHTF18 p.Leu541Phe (c.1621C>T) in the general population?

CHTF18 p.Leu541Phe (c.1621C>T) is ultra-rare (popmax 0.0292%, nfe) (gnomAD).

What do computational predictors say about CHTF18 p.Leu541Phe (c.1621C>T)?

AlphaMissense predicts ambiguous (score 0.5099) — an in-silico prediction, not a clinical call.

CHTF18 p.Leu541Phe

c.1621C>T · rs199836407 · VCV2232582

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5099 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0292%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5099	ambiguous
REVEL	0.348	indeterminate
SaProt	LLR -13.27	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	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	24.4	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 0.0292% European (non-Finnish) · 336/1,151,902 alleles

Filtering AF 0.0266% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0256%

Overall 0.0229% 357/1,559,630 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0292%	3,428
African / African-American	0.0123%	8,161
Finnishnot grpmax-eligible	0.0085%	11,770
Remaining individualsnot grpmax-eligible	0.00829%	12,056
East Asian	0.00245%	40,778
Admixed American	0.00186%	53,836

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.Leu541Phe
Coding: c.1621C>T
MANE Select: NM_022092
dbSNP: rs199836407
Type: single nucleotide variant
Location: chr16:793014 (GRCh38)
Gene constraint: LOEUF 1.712 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.97 · 10 PDB
Residue 541: an α-helix

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

Similar variants

CHTF18 p.Leu541= Benign ★★ 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.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-leu541phe (accessed [today's date]).

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