Is AMER3 p.Arg130His (c.389G>A) pathogenic?

AMER3 p.Arg130His (c.389G>A) is classified Uncertain significance in AMER3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-15). AlphaMissense: likely benign (0.2967); Rare (popmax 0.192%, eas).

How common is AMER3 p.Arg130His (c.389G>A) in the general population?

AMER3 p.Arg130His (c.389G>A) is rare (popmax 0.192%, eas) (gnomAD).

What do computational predictors say about AMER3 p.Arg130His (c.389G>A)?

AlphaMissense predicts likely benign (score 0.2967) — an in-silico prediction, not a clinical call.

AMER3 p.Arg130His

c.389G>A · rs141992347 · VCV2597334

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2967 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.192%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2967	likely benign
REVEL	0.169	moderately benign-leaning
SaProt	LLR -7.09	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 9.8	GERP 0.7, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 2,582 bp · p 0.068 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.192% East Asian · 86/44,882 alleles

Filtering AF 0.159% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.147%

Overall 0.00595% 96/1,613,068 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.192%	522
Remaining individualsnot grpmax-eligible	0.008%	12,498
Finnishnot grpmax-eligible	0.00159%	62,940
European (non-Finnish)	0.000339%	294,997

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: AMER3
Protein: p.Arg130His
Coding: c.389G>A
MANE Select: NM_152698
dbSNP: rs141992347
Type: single nucleotide variant
Location: chr2:130762461 (GRCh38)
Structure: AlphaFold pLDDT 45.30

Full AMER3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AMER3 p.Arg130Cys Uncertain significance ★ ⚠ same residue
AMER3 p.Ala175Val Uncertain significance ★ ⚠ same type
AMER3 p.Ala25Thr Uncertain significance ★ ⚠ same type
AMER3 p.Ala345Ser Uncertain significance ★ ⚠ same type
AMER3 p.Ala402Asp Uncertain significance ★ ⚠ same type
AMER3 p.Ala557Thr Uncertain significance ★ ⚠ same type
AMER3 p.Ala55Thr Uncertain significance ★ ⚠ same type
AMER3 p.Ala579Thr 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/amer3-p-arg130his (accessed [today's date]).

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