Is AMER2 p.Ala219Val (c.656C>T) pathogenic?

AMER2 p.Ala219Val (c.656C>T) is classified Uncertain significance in AMER2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-23). AlphaMissense: likely benign (0.089); Ultra-rare (popmax 0.0177%, mid).

How common is AMER2 p.Ala219Val (c.656C>T) in the general population?

AMER2 p.Ala219Val (c.656C>T) is ultra-rare (popmax 0.0177%, mid) (gnomAD).

What do computational predictors say about AMER2 p.Ala219Val (c.656C>T)?

AlphaMissense predicts likely benign (score 0.089) — an in-silico prediction, not a clinical call.

AMER2 p.Ala219Val

c.656C>T · rs373180945 · VCV2401627

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.089 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0177%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.089	likely benign
REVEL	0.098	moderately benign-leaning
SaProt	LLR -7.49	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 6.5	GERP 0.85, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,012 bp · p 0.5 · regional, not allelic
Overall
CADD	20.5	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 0.0177% Middle Eastern · 1/5,650 alleles

Filtering AF 0.00762% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00712%

Overall 0.00772% 119/1,541,090 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0193%	5,185
Middle Easterngrpmax	0.0177%	5,650
European (non-Finnish)	0.00907%	11,029
Remaining individualsnot grpmax-eligible	0.00338%	29,600
African / African-American	0.00143%	70,090

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala219Val
Coding: c.656C>T
MANE Select: NM_152704
dbSNP: rs373180945
Type: single nucleotide variant
Location: chr13:25170964 (GRCh38)
Gene constraint: LOEUF 0.655 · pLI 0.84 (gnomAD)
Structure: AlphaFold pLDDT 51.91
Residue 219: 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.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-ala219val (accessed [today's date]).

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