Is CHTF18 p.Ser222Phe (c.665C>T) pathogenic?

CHTF18 p.Ser222Phe (c.665C>T) is classified Uncertain significance in CHTF18 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-24). AlphaMissense: ambiguous (0.3769); Very rare (popmax 0.00535%, nfe).

How common is CHTF18 p.Ser222Phe (c.665C>T) in the general population?

CHTF18 p.Ser222Phe (c.665C>T) is very rare (popmax 0.00535%, nfe) (gnomAD).

What do computational predictors say about CHTF18 p.Ser222Phe (c.665C>T)?

AlphaMissense predicts ambiguous (score 0.3769) — an in-silico prediction, not a clinical call.

CHTF18 p.Ser222Phe

c.665C>T · VCV3833354

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3769 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00535%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3769	ambiguous
REVEL	0.11	moderately benign-leaning
SaProt	LLR -13.74	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.8	GERP 1.1, phastCons 0.78
Regional constraint	o/e 1.43	unconstrained · MANE · 9,287 bp · p 1.1e-58 · regional, not allelic
Overall
CADD	24.1	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 0.00535% European (non-Finnish) · 63/1,177,410 alleles

Filtering AF 0.00427% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00388%

Overall 0.00405% 65/1,606,410 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00535%	18,689
East Asian	0.00224%	44,586
South Asian	0.00111%	89,796

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.Ser222Phe
Coding: c.665C>T
MANE Select: NM_022092
Type: single nucleotide variant
Location: chr16:790235 (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-ser222phe (accessed [today's date]).

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