Is AMN p.Arg323Leu (c.968G>T) pathogenic?

AMN p.Arg323Leu (c.968G>T) is classified Uncertain significance in AMN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-01). AlphaMissense: likely benign (0.0998); Very rare (popmax 0.00166%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AMN p.Arg323Leu (c.968G>T)?

AMN p.Arg323Leu (c.968G>T) is associated with Inborn genetic diseases (ClinVar).

How common is AMN p.Arg323Leu (c.968G>T) in the general population?

AMN p.Arg323Leu (c.968G>T) is very rare (popmax 0.00166%, nfe) (gnomAD).

What do computational predictors say about AMN p.Arg323Leu (c.968G>T)?

AlphaMissense predicts likely benign (score 0.0998) — an in-silico prediction, not a clinical call.

AMN p.Arg323Leu

c.968G>T · rs1248355711 · VCV2331376

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0998 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00166%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0998	likely benign
REVEL	0.274	benign-leaning
SaProt	LLR -9.59	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.8	GERP -0.13, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 7,988 bp · p 0.14 · regional, not allelic
Overall
CADD	19.48	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00166% European (non-Finnish) · 19/1,146,644 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000854%

Overall 0.00123% 19/1,547,368 alleles · very rare exomes 19/1,395,106 · genomes 0/152,262 · 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.Arg323Leu
Coding: c.968G>T
MANE Select: NM_030943
dbSNP: rs1248355711
Type: single nucleotide variant
Location: chr14:102930048 (GRCh38)
Gene constraint: LOEUF 1.446 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.78 · 1 PDB
Residue 323: an α-helix

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

AMN p.Arg323Pro Uncertain significance ★ ⚠ same residue
AMN p.Arg323= Likely benign ★★ same residue
AMN p.Arg323Trp Uncertain significance ★ ⚠ same residue
AMN p.Ala238Thr Uncertain significance ★★ ⚠ same condition
AMN p.Ala44Thr Uncertain significance ★★ ⚠ same condition
AMN p.Arg271Trp Uncertain significance ★★ ⚠ same condition
AMN p.Arg424Gly Uncertain significance ★★ ⚠ same condition
AMN p.Cys250Trp 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-arg323leu (accessed [today's date]).

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