Is AMER2 p.Ala214Pro (c.640G>C) pathogenic?

AMER2 p.Ala214Pro (c.640G>C) is classified Uncertain significance in AMER2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-23). AlphaMissense: likely benign (0.0895); Very rare (popmax 0.00808%, nfe).

How common is AMER2 p.Ala214Pro (c.640G>C) in the general population?

AMER2 p.Ala214Pro (c.640G>C) is very rare (popmax 0.00808%, nfe) (gnomAD).

What do computational predictors say about AMER2 p.Ala214Pro (c.640G>C)?

AlphaMissense predicts likely benign (score 0.0895) — an in-silico prediction, not a clinical call.

AMER2 p.Ala214Pro

c.640G>C · rs577045065 · VCV2514038

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0895 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00808%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0895	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -6.94	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 2.6	GERP -0.016, phastCons 0.04
Regional constraint	o/e 1.02	unconstrained · MANE · 2,012 bp · p 0.5 · regional, not allelic
Overall
CADD	14.52	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 0.00808% European (non-Finnish) · 93/1,151,686 alleles

Filtering AF 0.00672% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00623%

Overall 0.00637% 99/1,553,506 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00808%	12,384
Finnishnot grpmax-eligible	0.00502%	19,931
South Asian	0.00233%	42,872
Remaining individualsnot grpmax-eligible	0.00167%	59,768

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.Ala214Pro
Coding: c.640G>C
MANE Select: NM_152704
dbSNP: rs577045065
Type: single nucleotide variant
Location: chr13:25170980 (GRCh38)
Gene constraint: LOEUF 0.655 · pLI 0.84 (gnomAD)
Structure: AlphaFold pLDDT 51.91
Residue 214: 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.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
AMER2 p.Ala324Thr 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-ala214pro (accessed [today's date]).

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