Is CHTF18 p.Phe916Tyr (c.2747T>A) pathogenic?

CHTF18 p.Phe916Tyr (c.2747T>A) is classified Uncertain significance in CHTF18 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: ambiguous (0.4827); Ultra-rare (popmax 0.0176%, nfe).

How common is CHTF18 p.Phe916Tyr (c.2747T>A) in the general population?

CHTF18 p.Phe916Tyr (c.2747T>A) is ultra-rare (popmax 0.0176%, nfe) (gnomAD).

What do computational predictors say about CHTF18 p.Phe916Tyr (c.2747T>A)?

AlphaMissense predicts ambiguous (score 0.4827) — an in-silico prediction, not a clinical call.

CHTF18 p.Phe916Tyr

c.2747T>A · rs772539974 · VCV2599966

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4827 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4827	ambiguous
REVEL	0.217	benign-leaning
SaProt	LLR -8.33	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2, phastCons 1
Regional constraint	o/e 1.43	unconstrained · MANE · 9,287 bp · p 1.1e-58 · regional, not allelic
Overall
CADD	25.1	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 0.0176% European (non-Finnish) · 208/1,179,452 alleles

Filtering AF 0.0156% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0149%

Overall 0.0137% 221/1,611,094 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0176%	5,670
Remaining individualsnot grpmax-eligible	0.0112%	8,910
Admixed American	0.00334%	29,966
Finnishnot grpmax-eligible	0.00319%	31,367
African / African-American	0.00268%	37,329

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.Phe916Tyr
Coding: c.2747T>A
MANE Select: NM_022092
dbSNP: rs772539974
Type: single nucleotide variant
Location: chr16:797707 (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-phe916tyr (accessed [today's date]).

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