Is AMER1 p.Arg894Cys (c.2680C>T) pathogenic?

AMER1 p.Arg894Cys (c.2680C>T) is classified Uncertain significance in AMER1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-12). AlphaMissense: ambiguous (0.5017); Very rare (popmax 0.00223%, nfe).

How common is AMER1 p.Arg894Cys (c.2680C>T) in the general population?

AMER1 p.Arg894Cys (c.2680C>T) is very rare (popmax 0.00223%, nfe) (gnomAD).

What do computational predictors say about AMER1 p.Arg894Cys (c.2680C>T)?

AlphaMissense predicts ambiguous (score 0.5017) — an in-silico prediction, not a clinical call.

AMER1 p.Arg894Cys

c.2680C>T · rs748618414 · VCV2988394

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5017 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5017	ambiguous
REVEL	0.335	indeterminate
SaProt	LLR -7.62	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 3,404 bp · p 0.037 · regional, not allelic
Overall
CADD	24.5	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 0.00223% European (non-Finnish) · 20/895,313 alleles

Filtering AF 0.00146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00119%

Overall 0.00173% 21/1,210,457 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00223%	44,766
African / African-American	0.00175%	57,278

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: AMER1
Protein: p.Arg894Cys
Coding: c.2680C>T
MANE Select: NM_152424
dbSNP: rs748618414
Type: single nucleotide variant
Location: chrX:64190607 (GRCh38)
Structure: AlphaFold pLDDT 48.88 · 3 PDB

Full AMER1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AMER1 p.Arg894His Likely benign ★ same residue
AMER1 p.Arg353Ter Pathogenic ★★ same type
AMER1 p.Arg358Ter Pathogenic ★★ same type
AMER1 p.Arg497Ter Pathogenic/Likely pathogenic ★★ same type
AMER1 p.Gln189Ter Pathogenic ★★ same type
AMER1 p.Gln335Ter Pathogenic ★★ same type
AMER1 p.Glu191Ter Pathogenic/Likely pathogenic ★★ same type
AMER1 p.Ala202Gly Uncertain significance ★★ ⚠ same type

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-arg894cys (accessed [today's date]).

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