Is AMER2 p.Arg209Pro (c.626G>C) pathogenic?

AMER2 p.Arg209Pro (c.626G>C) is classified Uncertain significance in AMER2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely benign (0.1197); Very rare (popmax 0.00231%, sas).

How common is AMER2 p.Arg209Pro (c.626G>C) in the general population?

AMER2 p.Arg209Pro (c.626G>C) is very rare (popmax 0.00231%, sas) (gnomAD).

What do computational predictors say about AMER2 p.Arg209Pro (c.626G>C)?

AlphaMissense predicts likely benign (score 0.1197) — an in-silico prediction, not a clinical call.

AMER2 p.Arg209Pro

c.626G>C · VCV4091273

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1197 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00231%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1197	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -6.17	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 5.1	GERP 0.99, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,012 bp · p 0.5 · regional, not allelic
Overall
CADD	22.4	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 0.00231% South Asian · 2/86,692 alleles

Filtering AF 0.000383% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000143%

Overall 0.000447% 7/1,564,426 alleles · very rare exomes 7/1,412,292 · genomes 0/152,134 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00231%	43,346
African / African-American	0.00141%	71,034
European (non-Finnish)	0.000346%	289,239

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: AMER2
Protein: p.Arg209Pro
Coding: c.626G>C
MANE Select: NM_152704
Type: single nucleotide variant
Location: chr13:25170994 (GRCh38)
Gene constraint: LOEUF 0.655 · pLI 0.84 (gnomAD)
Structure: AlphaFold pLDDT 51.91
Residue 209: the 'disordered' region

Full AMER2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AMER2 p.Ala158Gly Uncertain significance ★ ⚠ same type
AMER2 p.Ala158Pro Uncertain significance ★ ⚠ same type
AMER2 p.Ala212Val Uncertain significance ★ ⚠ same type
AMER2 p.Ala214Pro Uncertain significance ★ ⚠ same type
AMER2 p.Ala219Val Uncertain significance ★ ⚠ same type
AMER2 p.Ala245Ser Uncertain significance ★ ⚠ same type
AMER2 p.Ala260Glu Uncertain significance ★ ⚠ same type
AMER2 p.Ala319Pro 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/amer2-p-arg209pro (accessed [today's date]).

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