Is AMER1 p.Arg549Trp (c.1645C>T) pathogenic?

AMER1 p.Arg549Trp (c.1645C>T) is classified Likely benign in AMER1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-10). AlphaMissense: likely benign (0.2086); Ultra-rare (popmax 0.013%, amr).

How common is AMER1 p.Arg549Trp (c.1645C>T) in the general population?

AMER1 p.Arg549Trp (c.1645C>T) is ultra-rare (popmax 0.013%, amr) (gnomAD).

What do computational predictors say about AMER1 p.Arg549Trp (c.1645C>T)?

AlphaMissense predicts likely benign (score 0.2086) — an in-silico prediction, not a clinical call.

AMER1 p.Arg549Trp

c.1645C>T · rs746279756 · VCV2419207

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2086 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.013%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2086	likely benign
REVEL	0.185	benign-leaning
SaProt	LLR -7.78	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 1.5	GERP 0.73, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 3,404 bp · p 0.037 · regional, not allelic
Overall
CADD	21.7	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 0.013% Admixed American · 6/46,143 alleles

Filtering AF 0.00566% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00386%

Overall 0.00264% 29/1,098,249 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.013%	7,690
Ashkenazi Jewishnot grpmax-eligible	0.00907%	11,023
European (non-Finnish)	0.00223%	44,781
South Asian	0.00175%	57,017

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.Arg549Trp
Coding: c.1645C>T
MANE Select: NM_152424
dbSNP: rs746279756
Type: single nucleotide variant
Location: chrX:64191642 (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.Arg549Pro Uncertain significance ★ ⚠ same residue
AMER1 p.Arg549Gln 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

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-arg549trp (accessed [today's date]).

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