Is AMER1 p.Pro300Thr (c.898C>A) pathogenic?

AMER1 p.Pro300Thr (c.898C>A) is classified Benign in AMER1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-19). AlphaMissense: likely benign (0.0724); Ultra-rare (popmax 0.0103%, nfe).

How common is AMER1 p.Pro300Thr (c.898C>A) in the general population?

AMER1 p.Pro300Thr (c.898C>A) is ultra-rare (popmax 0.0103%, nfe) (gnomAD).

What do computational predictors say about AMER1 p.Pro300Thr (c.898C>A)?

AlphaMissense predicts likely benign (score 0.0724) — an in-silico prediction, not a clinical call.

AMER1 p.Pro300Thr

c.898C>A · rs745954685 · VCV1653403

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0724 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0724	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -6.54	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 4.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 3,404 bp · p 0.037 · regional, not allelic
Overall
CADD	20.4	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 0.0103% European (non-Finnish) · 92/895,418 alleles

Filtering AF 0.00853% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00791%

Overall 0.00793% 96/1,211,108 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0103%	9,733
Finnishnot grpmax-eligible	0.00427%	23,407
Admixed American	0.00217%	45,989
Remaining individualsnot grpmax-eligible	0.0021%	47,623

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.Pro300Thr
Coding: c.898C>A
MANE Select: NM_152424
dbSNP: rs745954685
Type: single nucleotide variant
Location: chrX:64192389 (GRCh38)
Structure: AlphaFold pLDDT 48.88 · 3 PDB
Residue 300: the 'disordered' region

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

Similar variants

AMER1 p.Pro300Leu 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
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-pro300thr (accessed [today's date]).

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