Is AMER1 p.Arg646Trp (c.1936C>T) pathogenic?

AMER1 p.Arg646Trp (c.1936C>T) is classified Benign/Likely benign in AMER1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-05). AlphaMissense: likely benign (0.0681); Ultra-rare (popmax 0.0178%, eas).

How common is AMER1 p.Arg646Trp (c.1936C>T) in the general population?

AMER1 p.Arg646Trp (c.1936C>T) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about AMER1 p.Arg646Trp (c.1936C>T)?

AlphaMissense predicts likely benign (score 0.0681) — an in-silico prediction, not a clinical call.

AMER1 p.Arg646Trp

c.1936C>T · rs775711054 · VCV751476

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0681 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0681	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -8.06	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 0.089	GERP -3.7
Regional constraint	o/e 1.07	unconstrained · MANE · 3,404 bp · p 0.037 · regional, not allelic
Overall
CADD	1.069	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 0.0178% East Asian · 6/33,789 alleles

Filtering AF 0.00765% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00527%

Overall 0.00082% 9/1,098,211 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,631
South Asian	0.00352%	28,447
European (non-Finnish)	0.000112%	895,480

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.Arg646Trp
Coding: c.1936C>T
MANE Select: NM_152424
dbSNP: rs775711054
Type: single nucleotide variant
Location: chrX:64191351 (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.Arg646Pro Benign ★ ⚠ same residue
AMER1 p.Arg646Gln Uncertain significance ⚠ 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-arg646trp (accessed [today's date]).

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