Is AMER1 p.Ser45= (c.135C>T) pathogenic?

AMER1 p.Ser45= (c.135C>T) is classified Benign in AMER1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-02). Common (popmax 9.1%, mid) — too common for a highly-penetrant pathogenic allele.

AMER1 p.Ser45=

Q: How common is AMER1 p.Ser45= (c.135C>T) in the general population?

AMER1 p.Ser45= (c.135C>T) is common (popmax 9.1%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.135C>T · rs34504794 · VCV1670165

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 9.1%, mid) — too common for a highly-penetrant pathogenic allele

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 0.062	GERP -2.6, phastCons 0.27
Overall
CADD	1.079	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.1% Middle Eastern · 395/4,342 alleles

Filtering AF 8.36% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.07%

Overall 0.932% 11,285/1,210,363 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	9.1%	11
Ashkenazi Jewishnot grpmax-eligible	6.32%	16
Finnishnot grpmax-eligible	3.56%	28
Remaining individualsnot grpmax-eligible	1.44%	69
European (non-Finnish)	0.732%	137
Admixed American	0.653%	153
South Asian	0.366%	273
African / African-American	0.157%	637

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.Ser45=
Coding: c.135C>T
MANE Select: NM_152424
dbSNP: rs34504794
Type: single nucleotide variant
Location: chrX:64193152 (GRCh38)
Structure: AlphaFold pLDDT 48.88 · 3 PDB
Residue 45: the 'disordered' region

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-ser45 (accessed [today's date]).

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