Is AMER1 p.Pro248Thr (c.742C>A) pathogenic?

AMER1 p.Pro248Thr (c.742C>A) is classified Benign/Likely benign in AMER1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-18). AlphaMissense: likely benign (0.0604); Ultra-rare (popmax 0.0254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with AMER1 p.Pro248Thr (c.742C>A)?

AMER1 p.Pro248Thr (c.742C>A) is associated with Inborn genetic diseases, osteopathia striata with cranial sclerosis (ClinVar).

How common is AMER1 p.Pro248Thr (c.742C>A) in the general population?

AMER1 p.Pro248Thr (c.742C>A) is ultra-rare (popmax 0.0254%, nfe) (gnomAD).

What do computational predictors say about AMER1 p.Pro248Thr (c.742C>A)?

AlphaMissense predicts likely benign (score 0.0604) — an in-silico prediction, not a clinical call.

AMER1 p.Pro248Thr

c.742C>A · rs149688443 · VCV792933

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0604 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0604	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -6.81	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 0.39	GERP -1.3, phastCons 0.016
Regional constraint	o/e 1.07	unconstrained · MANE · 3,404 bp · p 0.037 · regional, not allelic
Overall
CADD	1.123	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 0.0254% European (non-Finnish) · 227/893,189 alleles

Filtering AF 0.0226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0216%

Overall 0.0196% 236/1,203,731 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0254%	3,935
Remaining individualsnot grpmax-eligible	0.0106%	9,450
Admixed American	0.0045%	22,213
African / African-American	0.0035%	28,534

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.Pro248Thr
Coding: c.742C>A
MANE Select: NM_152424
dbSNP: rs149688443
Type: single nucleotide variant
Location: chrX:64192545 (GRCh38)
Structure: AlphaFold pLDDT 48.88 · 3 PDB
Residue 248: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: osteopathia striata with cranial sclerosis

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.Ala202Gly Uncertain significance ★★ ⚠ same condition
AMER1 p.Arg1113Met Uncertain significance ★★ ⚠ same condition
AMER1 p.Arg586Gln 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-pro248thr (accessed [today's date]).

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