Is AMER1 p.Glu758Val (c.2273A>T) pathogenic?

AMER1 p.Glu758Val (c.2273A>T) is classified Uncertain significance in AMER1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-15). AlphaMissense: likely benign (0.119); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with AMER1 p.Glu758Val (c.2273A>T)?

AMER1 p.Glu758Val (c.2273A>T) is associated with Inborn genetic diseases (ClinVar).

How common is AMER1 p.Glu758Val (c.2273A>T) in the general population?

AMER1 p.Glu758Val (c.2273A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AMER1 p.Glu758Val (c.2273A>T)?

AlphaMissense predicts likely benign (score 0.119) — an in-silico prediction, not a clinical call.

AMER1 p.Glu758Val

c.2273A>T · rs2147086452 · VCV2484405

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.119 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.119	likely benign
REVEL	0.125	moderately benign-leaning
SaProt	LLR -8.69	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP -0.94, phastCons 0.99
Regional constraint	o/e 1.07	unconstrained · MANE · 3,404 bp · p 0.037 · regional, not allelic
Overall
CADD	19.11	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AMER1
Protein: p.Glu758Val
Coding: c.2273A>T
MANE Select: NM_152424
dbSNP: rs2147086452
Type: single nucleotide variant
Location: chrX:64191014 (GRCh38)
Structure: AlphaFold pLDDT 48.88 · 3 PDB
Residue 758: the 'disordered' region

Full AMER1 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

AMER1 p.Arg353Ter Pathogenic ★★ same condition
AMER1 p.Arg358Ter Pathogenic ★★ same condition
AMER1 p.Ala202Gly Uncertain significance ★★ ⚠ same condition
AMER1 p.Arg1113Met Uncertain significance ★★ ⚠ same condition
AMER1 p.Arg586Gln Uncertain significance ★★ ⚠ same condition
AMER1 p.Arg606Lys Uncertain significance ★★ ⚠ same condition
AMER1 p.Gly1083Val Uncertain significance ★★ ⚠ same condition
AMER1 p.Gly672Glu 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/amer1-p-glu758val (accessed [today's date]).

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