Is ACAD9 p.Pro616Ser (c.1846C>T) pathogenic?

ACAD9 p.Pro616Ser (c.1846C>T) is classified Conflicting classifications of pathogenicity in ACAD9 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-09-08). AlphaMissense: ambiguous (0.5052); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with ACAD9 p.Pro616Ser (c.1846C>T)?

ACAD9 p.Pro616Ser (c.1846C>T) is associated with Inborn genetic diseases, acyl-CoA dehydrogenase 9 deficiency (ClinVar).

How common is ACAD9 p.Pro616Ser (c.1846C>T) in the general population?

ACAD9 p.Pro616Ser (c.1846C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ACAD9 p.Pro616Ser (c.1846C>T)?

AlphaMissense predicts ambiguous (score 0.5052) — an in-silico prediction, not a clinical call.

ACAD9 p.Pro616Ser

c.1846C>T · rs863224845 · VCV242523

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.5052 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5052	ambiguous
REVEL	0.873	moderately pathogenic-leaning
SaProt	LLR -11.42	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 1.6, phastCons 0.1
Regional constraint	o/e 0.97	unconstrained · MANE · 33 kb · p 0.36 · regional, not allelic
Overall
CADD	23.5	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 0.00167% Admixed American · 1/60,020 alleles

Overall 0.000137% 2/1,461,852 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,020
European (non-Finnish)	8.47e-05%	1,179,998

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.Pro616Ser
Coding: c.1846C>T
MANE Select: NM_014049
dbSNP: rs863224845
Type: single nucleotide variant
Location: chr3:128912587 (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

Disease context

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

Also linked: acyl-CoA dehydrogenase 9 deficiency

Similar variants

ACAD9 c.1150-2A>G Likely pathogenic ★★ same condition
ACAD9 c.1278+1G>T Likely pathogenic ★★ same condition
ACAD9 c.1279-2A>C Likely pathogenic ★★ same condition
ACAD9 c.1358+2T>G Likely pathogenic ★★ same condition
ACAD9 c.1359-1G>A Pathogenic/Likely pathogenic ★★ same condition
ACAD9 c.1563+1G>A Pathogenic/Likely pathogenic ★★ same condition
ACAD9 c.1A>G Pathogenic/Likely pathogenic ★★ same condition
ACAD9 c.453+1G>A Likely pathogenic ★★ 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-pro616ser (accessed [today's date]).

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