Is AMER2 p.Ala158Pro (c.472G>C) pathogenic?

AMER2 p.Ala158Pro (c.472G>C) is classified Uncertain significance in AMER2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: ambiguous (0.5048); Low-frequency (popmax 2.33%, mid).

How common is AMER2 p.Ala158Pro (c.472G>C) in the general population?

AMER2 p.Ala158Pro (c.472G>C) is low-frequency (popmax 2.33%, mid) (gnomAD).

What do computational predictors say about AMER2 p.Ala158Pro (c.472G>C)?

AlphaMissense predicts ambiguous (score 0.5048) — an in-silico prediction, not a clinical call.

AMER2 p.Ala158Pro

c.472G>C · rs200352589 · VCV3115231

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5048 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.33%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5048	ambiguous
REVEL	0.22	benign-leaning
SaProt	LLR -5.61	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP -0.3, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,012 bp · p 0.5 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.33% Middle Eastern · 133/5,696 alleles

Filtering AF 2.01% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.89%

Overall 0.0874% 1,351/1,545,570 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	2.33%	43
Ashkenazi Jewishnot grpmax-eligible	0.424%	236
Admixed American	0.208%	481
Remaining individualsnot grpmax-eligible	0.188%	533
South Asian	0.0771%	1,298
European (non-Finnish)	0.0688%	1,453
African / African-American	0.0298%	3,355
Finnishnot grpmax-eligible	0.00976%	10,244

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.Ala158Pro
Coding: c.472G>C
MANE Select: NM_152704
dbSNP: rs200352589
Type: single nucleotide variant
Location: chr13:25171148 (GRCh38)
Gene constraint: LOEUF 0.655 · pLI 0.84 (gnomAD)
Structure: AlphaFold pLDDT 51.91
Residue 158: 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 residue
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
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-ala158pro (accessed [today's date]).

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