Is CHTF18 p.Asn491Ser (c.1472A>G) pathogenic?

CHTF18 p.Asn491Ser (c.1472A>G) is classified Uncertain significance in CHTF18 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-10-11). AlphaMissense: ambiguous (0.4917); Very rare (popmax 0.0023%, nfe).

How common is CHTF18 p.Asn491Ser (c.1472A>G) in the general population?

CHTF18 p.Asn491Ser (c.1472A>G) is very rare (popmax 0.0023%, nfe) (gnomAD).

What do computational predictors say about CHTF18 p.Asn491Ser (c.1472A>G)?

AlphaMissense predicts ambiguous (score 0.4917) — an in-silico prediction, not a clinical call.

CHTF18 p.Asn491Ser

c.1472A>G · VCV3492804

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4917 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0023%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4917	ambiguous
REVEL	0.517	indeterminate
SaProt	LLR -10.33	damaging
Splicing
SpliceAI	Δ0.22	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 1.43	unconstrained · MANE · 9,287 bp · p 1.1e-58 · regional, not allelic
Overall
CADD	26.2	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 0.0023% European (non-Finnish) · 27/1,174,536 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00182% 29/1,595,442 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00347%	28,840
European (non-Finnish)grpmax	0.0023%	43,501
Remaining individualsnot grpmax-eligible	0.00162%	61,706

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asn491Ser
Coding: c.1472A>G
MANE Select: NM_022092
Type: single nucleotide variant
Location: chr16:792584 (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-asn491ser (accessed [today's date]).

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