Is AMN p.Leu371Pro (c.1112T>C) pathogenic?

AMN p.Leu371Pro (c.1112T>C) is classified Uncertain significance in AMN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely benign (0.1499); Ultra-rare (popmax 0.0106%, afr); Associated with Inborn genetic diseases.

What condition is associated with AMN p.Leu371Pro (c.1112T>C)?

AMN p.Leu371Pro (c.1112T>C) is associated with Inborn genetic diseases (ClinVar).

How common is AMN p.Leu371Pro (c.1112T>C) in the general population?

AMN p.Leu371Pro (c.1112T>C) is ultra-rare (popmax 0.0106%, afr) (gnomAD).

What do computational predictors say about AMN p.Leu371Pro (c.1112T>C)?

AlphaMissense predicts likely benign (score 0.1499) — an in-silico prediction, not a clinical call.

AMN p.Leu371Pro

c.1112T>C · VCV4576207

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1499 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0106%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1499	likely benign
REVEL	0.566	indeterminate
SaProt	LLR -13.60	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -2, phastCons 0.79
Regional constraint	o/e 1.06	unconstrained · MANE · 7,988 bp · p 0.14 · regional, not allelic
Overall
CADD	24.7	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 0.0106% African / African-American · 7/66,124 alleles

Filtering AF 0.00489% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00352%

Overall 0.000506% 7/1,383,708 alleles · ultra-rare exomes 0/1,232,092 · genomes 7/151,616 · joint denominator

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: AMN
Protein: p.Leu371Pro
Coding: c.1112T>C
MANE Select: NM_030943
Type: single nucleotide variant
Location: chr14:102930270 (GRCh38)
Gene constraint: LOEUF 1.446 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.78 · 1 PDB

Full AMN 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

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AMN p.Arg424Gly Uncertain significance ★★ ⚠ same condition
AMN p.Cys250Trp Uncertain significance ★★ ⚠ same condition
AMN p.Gln288His Uncertain significance ★★ ⚠ same condition
AMN p.Pro444Ser Uncertain significance ★★ ⚠ same condition
AMN p.Ser437Asn 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/amn-p-leu371pro (accessed [today's date]).

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