Is AMER1 p.Arg646Pro (c.1937G>C) pathogenic?

AMER1 p.Arg646Pro (c.1937G>C) is classified Benign in AMER1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-08). AlphaMissense: likely benign (0.1878); Ultra-rare (popmax 0.035%, afr).

How common is AMER1 p.Arg646Pro (c.1937G>C) in the general population?

AMER1 p.Arg646Pro (c.1937G>C) is ultra-rare (popmax 0.035%, afr) (gnomAD).

What do computational predictors say about AMER1 p.Arg646Pro (c.1937G>C)?

AlphaMissense predicts likely benign (score 0.1878) — an in-silico prediction, not a clinical call.

AMER1 p.Arg646Pro

c.1937G>C · rs147754688 · VCV1583640

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1878 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1878	likely benign
REVEL	0.135	moderately benign-leaning
SaProt	LLR -15.85	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -3.7
Regional constraint	o/e 1.07	unconstrained · MANE · 3,404 bp · p 0.037 · regional, not allelic
Overall
CADD	0.696	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 0.035% African / African-American · 20/57,137 alleles

Filtering AF 0.0232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0194%

Overall 0.00174% 21/1,209,973 alleles · ultra-rare exomes 12/1,098,219 · genomes 9/111,754 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.035%	2,857
Middle Eastern	0.0229%	4,374

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.Arg646Pro
Coding: c.1937G>C
MANE Select: NM_152424
dbSNP: rs147754688
Type: single nucleotide variant
Location: chrX:64191350 (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.Arg646Trp Benign/Likely 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-arg646pro (accessed [today's date]).

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