Is AMACR p.Leu331= (c.993G>A) pathogenic?

AMACR p.Leu331= (c.993G>A) is classified Likely benign in AMACR (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-12-21). Very rare (popmax 0.00167%, amr); Associated with AMACR-related disorder.

What condition is associated with AMACR p.Leu331= (c.993G>A)?

AMACR p.Leu331= (c.993G>A) is associated with AMACR-related disorder (ClinVar).

How common is AMACR p.Leu331= (c.993G>A) in the general population?

AMACR p.Leu331= (c.993G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

AMACR p.Leu331=

c.993G>A · rs760727161 · VCV3050787

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

AMACR-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -3.6
Overall
CADD	2.632	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,020 alleles

Overall 0.000137% 2/1,461,862 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,020
European (non-Finnish)	8.47e-05%	1,179,999

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.Leu331=
Coding: c.993G>A
MANE Select: NM_014324
dbSNP: rs760727161
Type: single nucleotide variant
Location: chr5:33989249 (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

Similar variants

AMACR p.Ser52Pro Pathogenic/Likely pathogenic ★★ same condition
AMACR p.Pro296Leu Uncertain significance ★★ ⚠ same condition
AMACR p.Gly83Ser Likely pathogenic ★ same condition
AMACR p.Asp123Asn Conflicting classifications of pathogenicity ★ ⚠ same condition
AMACR p.Val304Phe Uncertain significance ★ ⚠ same condition
AMACR p.Arg40Gly Uncertain significance ⚠ same condition
AMACR p.Arg97Gln Uncertain significance ⚠ same condition
AMACR p.Ile353Leu 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-leu331 (accessed [today's date]).

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