Is ACAD9 p.Arg446Cys (c.1336C>T) pathogenic?

ACAD9 p.Arg446Cys (c.1336C>T) is classified Uncertain significance in ACAD9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-23). AlphaMissense: likely benign (0.1469); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

What condition is associated with ACAD9 p.Arg446Cys (c.1336C>T)?

ACAD9 p.Arg446Cys (c.1336C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ACAD9 p.Arg446Cys (c.1336C>T) in the general population?

ACAD9 p.Arg446Cys (c.1336C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about ACAD9 p.Arg446Cys (c.1336C>T)?

AlphaMissense predicts likely benign (score 0.1469) — an in-silico prediction, not a clinical call.

ACAD9 p.Arg446Cys

c.1336C>T · rs781520431 · VCV1204520

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1469 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1469	likely benign
REVEL	0.377	indeterminate
SaProt	LLR -11.55	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP 0.38
Regional constraint	o/e 0.97	unconstrained · MANE · 33 kb · p 0.36 · regional, not allelic
Overall
CADD	23.4	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 0.00446% East Asian · 2/44,892 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000682% 11/1,614,056 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,446
South Asian	0.00329%	30,364
African / African-American	0.00133%	74,940
European (non-Finnish)	0.000424%	236,007

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.Arg446Cys
Coding: c.1336C>T
MANE Select: NM_014049
dbSNP: rs781520431
Type: single nucleotide variant
Location: chr3:128908242 (GRCh38)
Gene constraint: LOEUF 0.884 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.09 · 2 PDB
Residue 446: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACAD9 p.Arg446His Uncertain significance ★★ ⚠ same residue
ACAD9 c.1149+5C>A Uncertain significance ★★ same condition
ACAD9 p.Ala397Val Uncertain significance ★★ ⚠ same condition
ACAD9 p.Ala495= Uncertain significance ★★ same condition
ACAD9 p.Ala495Val Uncertain significance ★★ ⚠ same condition
ACAD9 p.Ala545Gly Uncertain significance ★★ ⚠ same condition
ACAD9 p.Arg31Cys Uncertain significance ★★ ⚠ same condition
ACAD9 p.Arg420His Uncertain significance ★★ ⚠ same condition

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-arg446cys (accessed [today's date]).

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