Is ACADM p.Ile396Val (c.1186A>G) pathogenic?

ACADM p.Ile396Val (c.1186A>G) is classified Uncertain significance in ACADM (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-01). AlphaMissense: ambiguous (0.5128); Very rare (popmax 0.000254%, nfe).

How common is ACADM p.Ile396Val (c.1186A>G) in the general population?

ACADM p.Ile396Val (c.1186A>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about ACADM p.Ile396Val (c.1186A>G)?

AlphaMissense predicts ambiguous (score 0.5128) — an in-silico prediction, not a clinical call.

ACADM p.Ile396Val

c.1186A>G · rs1171321888 · VCV623689

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5128 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5128	ambiguous
REVEL	0.656	pathogenic-leaning
SaProt	LLR -9.95	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 0.65, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 38 kb · p 0.63 · 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 0.000254% European (non-Finnish) · 3/1,179,910 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,582 alleles · very rare

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: ACADM
Protein: p.Ile396Val
Coding: c.1186A>G
MANE Select: NM_000016
dbSNP: rs1171321888
Type: single nucleotide variant
Location: chr1:75761362 (GRCh38)
Gene constraint: LOEUF 1.072 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.15 · 7 PDB
Residue 396: an α-helix

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

Similar variants

ACADM p.Ile396Met Likely pathogenic ★ same residue
ACADM p.Ile396fs Pathogenic ★ same residue
ACADM c.118+1G>T Likely pathogenic ★★ same type
ACADM c.1194+1G>A Pathogenic/Likely pathogenic ★★ same type
ACADM c.1194+2T>G Likely pathogenic ★★ same type
ACADM c.216+1G>A Pathogenic ★★ same type
ACADM c.216+1G>T Pathogenic/Likely pathogenic ★★ same type
ACADM c.216+2T>C 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/acadm-p-ile396val (accessed [today's date]).

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