Is AMER1 p.Pro375Thr (c.1123C>A) pathogenic?

AMER1 p.Pro375Thr (c.1123C>A) is classified Uncertain significance in AMER1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-17). AlphaMissense: likely pathogenic (0.7766); Very rare (popmax 0.00176%, afr).

How common is AMER1 p.Pro375Thr (c.1123C>A) in the general population?

AMER1 p.Pro375Thr (c.1123C>A) is very rare (popmax 0.00176%, afr) (gnomAD).

What do computational predictors say about AMER1 p.Pro375Thr (c.1123C>A)?

AlphaMissense predicts likely pathogenic (score 0.7766) — an in-silico prediction, not a clinical call.

AMER1 p.Pro375Thr

c.1123C>A · rs1170189358 · VCV2735474

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7766 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00176%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7766	likely pathogenic · top 10% in AMER1
REVEL	0.288	benign-leaning
SaProt	LLR -6.00	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 3,404 bp · p 0.037 · regional, not allelic
Overall
CADD	23.8	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

Grpmax group 0.00176% African / African-American · 1/56,787 alleles

Overall 0.000902% 1/110,912 alleles · very rare

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.Pro375Thr
Coding: c.1123C>A
MANE Select: NM_152424
dbSNP: rs1170189358
Type: single nucleotide variant
Location: chrX:64192164 (GRCh38)
Structure: AlphaFold pLDDT 48.88 · 3 PDB
Residue 375: 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-pro375thr (accessed [today's date]).

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