Is ITM2B p.Pro31Arg (c.92C>G) pathogenic?

ITM2B p.Pro31Arg (c.92C>G) is classified Uncertain significance in ITM2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-24). AlphaMissense: likely benign (0.1048); Ultra-rare (popmax 0.0222%, amr); Associated with ABri amyloidosis.

What condition is associated with ITM2B p.Pro31Arg (c.92C>G)?

ITM2B p.Pro31Arg (c.92C>G) is associated with ABri amyloidosis, ADan amyloidosis, retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies (ClinVar).

How common is ITM2B p.Pro31Arg (c.92C>G) in the general population?

ITM2B p.Pro31Arg (c.92C>G) is ultra-rare (popmax 0.0222%, amr) (gnomAD).

How is Hereditary cerebral amyloid angiopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ITM2B p.Pro31Arg (c.92C>G)?

AlphaMissense predicts likely benign (score 0.1048) — an in-silico prediction, not a clinical call.

ITM2B p.Pro31Arg

c.92C>G · rs150336652 · VCV1353049

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1048 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0222%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABri amyloidosis

Computational evidence

Protein change
AlphaMissense	0.1048	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -7.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.7	GERP 1.3, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 28 kb · p 0.069 · regional, not allelic
Overall
CADD	19.93	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0222% Admixed American · 11/49,570 alleles

Filtering AF 0.0124% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00955%

Overall 0.0105% 162/1,535,992 alleles · ultra-rare exomes 154/1,383,796 · genomes 8/152,196 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0222%	4,506
Remaining individualsnot grpmax-eligible	0.0152%	6,591
European (non-Finnish)	0.0116%	8,657
African / African-American	0.00713%	14,028
South Asian	0.00487%	20,517
East Asian	0.00261%	38,298

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: ITM2B
Protein: p.Pro31Arg
Coding: c.92C>G
MANE Select: NM_021999
dbSNP: rs150336652
Type: single nucleotide variant
Location: chr13:48233452 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI 0.58 (gnomAD)
Structure: AlphaFold pLDDT 76.31 · 2 PDB

Full ITM2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ABri amyloidosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ADan amyloidosis retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies

For Hereditary cerebral amyloid angiopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

ITM2B p.Pro31Leu Uncertain significance ★ ⚠ same residue
ITM2B p.Pro31Ser Uncertain significance ★ ⚠ same residue
ITM2B p.Pro31Thr Uncertain significance ★ ⚠ same residue
ITM2B p.Pro31= Likely benign ★ same residue
ITM2B p.Ter267Leu Likely pathogenic ★★ same condition
ITM2B p.Lys17Arg Uncertain significance ★ ⚠ same condition
ITM2B p.Glu261Ala Pathogenic ⚠ same condition
ITM2B p.Ter267Arg Pathogenic 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/itm2b-p-pro31arg (accessed [today's date]).

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