Is AMER3 p.Arg709His (c.2126G>A) pathogenic?

AMER3 p.Arg709His (c.2126G>A) is classified Uncertain significance in AMER3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.0809); Ultra-rare (popmax 0.0179%, eas).

How common is AMER3 p.Arg709His (c.2126G>A) in the general population?

AMER3 p.Arg709His (c.2126G>A) is ultra-rare (popmax 0.0179%, eas) (gnomAD).

What do computational predictors say about AMER3 p.Arg709His (c.2126G>A)?

AlphaMissense predicts likely benign (score 0.0809) — an in-silico prediction, not a clinical call.

AMER3 p.Arg709His

c.2126G>A · rs562674707 · VCV2471630

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0809 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0179%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0809	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -6.80	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 -0.14	GERP -2.4
Regional constraint	o/e 1.05	unconstrained · MANE · 2,582 bp · p 0.068 · regional, not allelic
Overall
CADD	14.42	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 0.0179% East Asian · 8/44,744 alleles

Filtering AF 0.00886% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00643%

Overall 0.00155% 25/1,608,442 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0179%	5,593
African / African-American	0.00667%	14,995
South Asian	0.00332%	30,149
Admixed American	0.00168%	59,638
Remaining individualsnot grpmax-eligible	0.00161%	62,224
European (non-Finnish)	0.000595%	168,158

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.Arg709His
Coding: c.2126G>A
MANE Select: NM_152698
dbSNP: rs562674707
Type: single nucleotide variant
Location: chr2:130764198 (GRCh38)
Structure: AlphaFold pLDDT 45.30

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

Similar variants

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
AMER3 p.Ala588Pro 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-arg709his (accessed [today's date]).

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