Is AMER1 p.Ser1123Arg (c.3369C>G) pathogenic?

AMER1 p.Ser1123Arg (c.3369C>G) is classified Uncertain significance in AMER1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-12). AlphaMissense: ambiguous (0.4571); Absent from gnomAD v4.1; Associated with osteopathia striata with cranial sclerosis.

What condition is associated with AMER1 p.Ser1123Arg (c.3369C>G)?

AMER1 p.Ser1123Arg (c.3369C>G) is associated with osteopathia striata with cranial sclerosis (ClinVar).

How common is AMER1 p.Ser1123Arg (c.3369C>G) in the general population?

AMER1 p.Ser1123Arg (c.3369C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AMER1 p.Ser1123Arg (c.3369C>G)?

AlphaMissense predicts ambiguous (score 0.4571) — an in-silico prediction, not a clinical call.

AMER1 p.Ser1123Arg

c.3369C>G · rs1027220324 · VCV2431812

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4571 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

osteopathia striata with cranial sclerosis

Computational evidence

Protein change
AlphaMissense	0.4571	ambiguous
REVEL	0.068	moderately benign-leaning
SaProt	LLR -7.47	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 2.3	GERP 1.4, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 3,404 bp · p 0.037 · regional, not allelic
Overall
CADD	17.87	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AMER1
Protein: p.Ser1123Arg
Coding: c.3369C>G
MANE Select: NM_152424
dbSNP: rs1027220324
Type: single nucleotide variant
Location: chrX:64189918 (GRCh38)
Structure: AlphaFold pLDDT 48.88 · 3 PDB
Residue 1123: the 'disordered' region

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

Disease context

osteopathia striata with cranial sclerosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AMER1 p.Arg353Ter Pathogenic ★★ same condition
AMER1 p.Arg358Ter Pathogenic ★★ same condition
AMER1 p.Arg497Ter Pathogenic/Likely pathogenic ★★ same condition
AMER1 p.Gln189Ter Pathogenic ★★ same condition
AMER1 p.Gln335Ter Pathogenic ★★ same condition
AMER1 p.Arg77Trp Uncertain significance ★★ ⚠ same condition
AMER1 p.Gln213Arg Uncertain significance ★★ ⚠ same condition
AMER1 p.Gly435= Uncertain significance ★★ same condition

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-ser1123arg (accessed [today's date]).

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