Is AMER1 p.Ala449= (c.1347C>A) pathogenic?

AMER1 p.Ala449= (c.1347C>A) is classified Benign/Likely benign in AMER1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-17). Ultra-rare (popmax 0.0229%, mid).

How common is AMER1 p.Ala449= (c.1347C>A) in the general population?

AMER1 p.Ala449= (c.1347C>A) is ultra-rare (popmax 0.0229%, mid) (gnomAD).

AMER1 p.Ala449=

c.1347C>A · VCV3611631

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0229%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.53	GERP -3.7, phastCons 0.043
Overall
CADD	4.251	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0229% Middle Eastern · 1/4,367 alleles

Overall 0.0024% 29/1,209,973 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0579%	1,727
Middle Easterngrpmax	0.0229%	4,367
European (non-Finnish)	0.000112%	895,255

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: AMER1
Protein: p.Ala449=
Coding: c.1347C>A
MANE Select: NM_152424
Type: single nucleotide variant
Location: chrX:64191940 (GRCh38)
Structure: AlphaFold pLDDT 48.88 · 3 PDB
Residue 449: the 'disordered' region

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

Similar variants

AMER1 p.Ala449Gly Uncertain significance ★ ⚠ same residue
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

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-ala449 (accessed [today's date]).

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