Is AMER1 p.Pro953Ser (c.2857C>T) pathogenic?

AMER1 p.Pro953Ser (c.2857C>T) is classified Uncertain significance in AMER1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: likely benign (0.3044); Ultra-rare (popmax 0.0139%, afr).

How common is AMER1 p.Pro953Ser (c.2857C>T) in the general population?

AMER1 p.Pro953Ser (c.2857C>T) is ultra-rare (popmax 0.0139%, afr) (gnomAD).

What do computational predictors say about AMER1 p.Pro953Ser (c.2857C>T)?

AlphaMissense predicts likely benign (score 0.3044) — an in-silico prediction, not a clinical call.

AMER1 p.Pro953Ser

c.2857C>T · VCV3711685

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3044 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0139%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3044	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -6.26	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 8.2	GERP 1.7, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 3,404 bp · p 0.037 · regional, not allelic
Overall
CADD	21.4	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 0.0139% African / African-American · 8/57,385 alleles

Filtering AF 0.00688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00501%

Overall 0.000909% 11/1,210,419 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0139%	7,173
Admixed American	0.00436%	22,957
Remaining individualsnot grpmax-eligible	0.0021%	47,621

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: AMER1
Protein: p.Pro953Ser
Coding: c.2857C>T
MANE Select: NM_152424
Type: single nucleotide variant
Location: chrX:64190430 (GRCh38)
Structure: AlphaFold pLDDT 48.88 · 3 PDB

Full AMER1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AMER1 p.Arg353Ter Pathogenic ★★ same type
AMER1 p.Arg358Ter Pathogenic ★★ same type
AMER1 p.Arg497Ter Pathogenic/Likely pathogenic ★★ same type
AMER1 p.Gln189Ter Pathogenic ★★ same type
AMER1 p.Gln335Ter Pathogenic ★★ same type
AMER1 p.Glu191Ter Pathogenic/Likely pathogenic ★★ same type
AMER1 p.Ala202Gly Uncertain significance ★★ ⚠ same type
AMER1 p.Ala229Pro 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/amer1-p-pro953ser (accessed [today's date]).

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