Is AMER2 p.Pro263Ala (c.787C>G) pathogenic?

AMER2 p.Pro263Ala (c.787C>G) is classified Uncertain significance in AMER2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). AlphaMissense: likely benign (0.0587); Very rare (popmax 0.00296%, afr).

How common is AMER2 p.Pro263Ala (c.787C>G) in the general population?

AMER2 p.Pro263Ala (c.787C>G) is very rare (popmax 0.00296%, afr) (gnomAD).

What do computational predictors say about AMER2 p.Pro263Ala (c.787C>G)?

AlphaMissense predicts likely benign (score 0.0587) — an in-silico prediction, not a clinical call.

AMER2 p.Pro263Ala

c.787C>G · VCV3535173

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0587 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00296%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0587	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -6.07	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 5.3	GERP 0.99, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,012 bp · p 0.5 · regional, not allelic
Overall
CADD	16.92	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 0.00296% African / African-American · 2/67,598 alleles

Filtering AF 0.000491% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000184%

Overall 0.00014% 2/1,429,440 alleles · very rare exomes 1/1,277,472 · genomes 1/151,968 · joint denominator

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.Pro263Ala
Coding: c.787C>G
MANE Select: NM_152704
Type: single nucleotide variant
Location: chr13:25170833 (GRCh38)
Gene constraint: LOEUF 0.655 · pLI 0.84 (gnomAD)
Structure: AlphaFold pLDDT 51.91
Residue 263: 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-pro263ala (accessed [today's date]).

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