Is ITM2B p.Arg221Ter (c.661C>T) pathogenic?

ITM2B p.Arg221Ter (c.661C>T) is classified Uncertain significance in ITM2B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-03). Very rare (popmax 0.00167%, amr).

How common is ITM2B p.Arg221Ter (c.661C>T) in the general population?

ITM2B p.Arg221Ter (c.661C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

ITM2B p.Arg221Ter

c.661C>T · rs767045938 · VCV1957222

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 6
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.1	GERP 2.3, phastCons 1
Overall
CADD	38.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,986 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000682% 11/1,612,900 alleles · very rare exomes 11/1,460,646 · genomes 0/152,254 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,986
African / African-American	0.00133%	74,988
European (non-Finnish)	0.000763%	130,997

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.Arg221Ter
Coding: c.661C>T
MANE Select: NM_021999
dbSNP: rs767045938
Type: single nucleotide variant
Location: chr13:48258893 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI 0.58 (gnomAD)
Structure: AlphaFold pLDDT 76.31 · 2 PDB
Residue 221: an α-helix; the brichos domain

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

Similar variants

ITM2B p.Arg221Gln Uncertain significance ★★ ⚠ same residue
ITM2B p.Ter267Leu Likely pathogenic ★★ same type
ITM2B p.Ala62Val 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-arg221ter (accessed [today's date]).

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