Is ITM2B p.Pro31Ser (c.91C>T) pathogenic?

ITM2B p.Pro31Ser (c.91C>T) is classified Uncertain significance in ITM2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-08). AlphaMissense: likely benign (0.0853); Very rare (popmax 0.00201%, amr); Associated with Inborn genetic diseases.

What condition is associated with ITM2B p.Pro31Ser (c.91C>T)?

ITM2B p.Pro31Ser (c.91C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ITM2B p.Pro31Ser (c.91C>T) in the general population?

ITM2B p.Pro31Ser (c.91C>T) is very rare (popmax 0.00201%, amr) (gnomAD).

What do computational predictors say about ITM2B p.Pro31Ser (c.91C>T)?

AlphaMissense predicts likely benign (score 0.0853) — an in-silico prediction, not a clinical call.

ITM2B p.Pro31Ser

c.91C>T · VCV4040347

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0853 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00201%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0853	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -6.33	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 3.1	GERP 2.1, phastCons 0.99
Regional constraint	o/e 0.90	unconstrained · MANE · 28 kb · p 0.069 · regional, not allelic
Overall
CADD	19.84	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 0.00201% Admixed American · 1/49,702 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00026% 4/1,536,932 alleles · very rare exomes 2/1,384,860 · genomes 2/152,072 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00201%	49,702
South Asian	0.00122%	82,140
European (non-Finnish)	0.000175%	571,690

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.Pro31Ser
Coding: c.91C>T
MANE Select: NM_021999
Type: single nucleotide variant
Location: chr13:48233451 (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

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

Similar variants

ITM2B p.Pro31Arg Uncertain significance ★★ ⚠ same residue
ITM2B p.Pro31Leu Uncertain significance ★ ⚠ same residue
ITM2B p.Pro31Thr Uncertain significance ★ ⚠ same residue
ITM2B p.Pro31= Likely benign ★ same residue
ITM2B p.Arg233Cys Uncertain significance ★★ ⚠ same condition
ITM2B p.Asp85Asn Uncertain significance ★★ ⚠ same condition
ITM2B p.Glu126Val Uncertain significance ★★ ⚠ same condition
ITM2B p.His200Asp 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/itm2b-p-pro31ser (accessed [today's date]).

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