Is AMACR p.Pro296Leu (c.887C>T) pathogenic?

AMACR p.Pro296Leu (c.887C>T) is classified Uncertain significance in AMACR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-05-30). AlphaMissense: likely pathogenic (0.614); Very rare (popmax 0.00333%, amr); Associated with AMACR-related disorder.

What condition is associated with AMACR p.Pro296Leu (c.887C>T)?

AMACR p.Pro296Leu (c.887C>T) is associated with AMACR-related disorder, congenital bile acid synthesis defect 4, alpha-methylacyl-CoA racemase deficiency (ClinVar).

How common is AMACR p.Pro296Leu (c.887C>T) in the general population?

AMACR p.Pro296Leu (c.887C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about AMACR p.Pro296Leu (c.887C>T)?

AlphaMissense predicts likely pathogenic (score 0.614) — an in-silico prediction, not a clinical call.

AMACR p.Pro296Leu

c.887C>T · rs774180397 · VCV1413911

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.614 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

AMACR-related disorder

Computational evidence

Protein change
AlphaMissense	0.614	likely pathogenic
REVEL	0.679	pathogenic-leaning
SaProt	LLR -13.51	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 19 kb · p 0.71 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,004 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00161% 26/1,614,040 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,002
South Asian	0.0022%	45,539
European (non-Finnish)	0.00186%	53,638

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: AMACR
Protein: p.Pro296Leu
Coding: c.887C>T
MANE Select: NM_014324
dbSNP: rs774180397
Type: single nucleotide variant
Location: chr5:33989355 (GRCh38)
Gene constraint: LOEUF 1.239 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.79

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

Disease context

AMACR-related disorder

Also linked: congenital bile acid synthesis defect 4 alpha-methylacyl-CoA racemase deficiency

Similar variants

AMACR p.Pro296= Likely benign ★ same residue
AMACR p.Ser52Pro Pathogenic/Likely pathogenic ★★ same condition
AMACR c.*233T>C Uncertain significance ★★ same condition
AMACR p.Ala15Pro Uncertain significance ★★ ⚠ same condition
AMACR p.Ala189Glu Uncertain significance ★★ ⚠ same condition
AMACR p.Arg106Lys Uncertain significance ★★ ⚠ same condition
AMACR p.Arg171Cys Uncertain significance ★★ ⚠ same condition
AMACR p.Arg171His 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/amacr-p-pro296leu (accessed [today's date]).

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