Is ITM2B p.Phe258= (c.774T>C) pathogenic?

ITM2B p.Phe258= (c.774T>C) is classified Conflicting classifications of pathogenicity in ITM2B (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-01). Ultra-rare (popmax 0.0331%, mid).

How common is ITM2B p.Phe258= (c.774T>C) in the general population?

ITM2B p.Phe258= (c.774T>C) is ultra-rare (popmax 0.0331%, mid) (gnomAD).

ITM2B p.Phe258=

c.774T>C · rs144217555 · VCV807008

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0331%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.4	GERP 2.4, phastCons 1
Overall
CADD	8.373	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0331% Middle Eastern · 2/6,044 alleles

Filtering AF 0.0298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0287%

Overall 0.0264% 426/1,612,182 alleles · ultra-rare exomes 379/1,459,894 · genomes 47/152,288 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.54%	65
Middle Easterngrpmax	0.0331%	3,022
European (non-Finnish)	0.0325%	3,077
Remaining individualsnot grpmax-eligible	0.0224%	4,459
Finnishnot grpmax-eligible	0.0156%	6,398
African / African-American	0.00267%	37,488
Admixed American	0.00167%	59,962

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe258=
Coding: c.774T>C
MANE Select: NM_021999
dbSNP: rs144217555
Type: single nucleotide variant
Location: chr13:48261197 (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

Similar variants

ITM2B p.Ter267Leu Likely pathogenic ★★ same type
ITM2B p.Ala62Val Uncertain significance ★★ ⚠ same type
ITM2B p.Arg221Gln Uncertain significance ★★ ⚠ same type
ITM2B p.Arg233Cys Uncertain significance ★★ ⚠ same type
ITM2B p.Asp85Asn Uncertain significance ★★ ⚠ same type
ITM2B p.Glu126Val Uncertain significance ★★ ⚠ same type
ITM2B p.Glu19Lys Uncertain significance ★★ ⚠ same type
ITM2B p.His200Asp 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/itm2b-p-phe258 (accessed [today's date]).

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