Is ACAD9 p.Arg15Cys (c.43C>T) pathogenic?

ACAD9 p.Arg15Cys (c.43C>T) is classified Likely pathogenic in ACAD9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-23). AlphaMissense: ambiguous (0.4175); Ultra-rare (popmax 0.0171%, mid).

How common is ACAD9 p.Arg15Cys (c.43C>T) in the general population?

ACAD9 p.Arg15Cys (c.43C>T) is ultra-rare (popmax 0.0171%, mid) (gnomAD).

What do computational predictors say about ACAD9 p.Arg15Cys (c.43C>T)?

AlphaMissense predicts ambiguous (score 0.4175) — an in-silico prediction, not a clinical call.

ACAD9 p.Arg15Cys

c.43C>T · rs745759890 · VCV1493882

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4175 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0171%, mid)

Computational evidence

Protein change
AlphaMissense	0.4175	ambiguous
REVEL	0.577	indeterminate
SaProt	LLR -7.44	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.47	GERP 1.6, phastCons 0.59
Regional constraint	o/e 0.97	unconstrained · MANE · 33 kb · p 0.36 · regional, not allelic
Overall
CADD	21.9	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 0.0171% Middle Eastern · 1/5,852 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00192% 28/1,460,548 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0171%	5,852
South Asian	0.00878%	11,383
Remaining individualsnot grpmax-eligible	0.0048%	20,820
European (non-Finnish)	0.00136%	73,747

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: ACAD9
Protein: p.Arg15Cys
Coding: c.43C>T
MANE Select: NM_014049
dbSNP: rs745759890
Type: single nucleotide variant
Location: chr3:128879734 (GRCh38)
Gene constraint: LOEUF 0.884 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.09 · 2 PDB

Full ACAD9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACAD9 p.Arg15Pro Uncertain significance ★ ⚠ same residue
ACAD9 p.Arg15= Likely benign ★ same residue
ACAD9 c.1030-1G>A Pathogenic/Likely pathogenic ★★ same type
ACAD9 c.1150-2A>G Likely pathogenic ★★ same type
ACAD9 c.1278+1G>T Likely pathogenic ★★ same type
ACAD9 c.1279-2A>C Likely pathogenic ★★ same type
ACAD9 c.1358+2T>G Likely pathogenic ★★ same type
ACAD9 c.1359-1G>A Pathogenic/Likely pathogenic ★★ 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/acad9-p-arg15cys (accessed [today's date]).

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