Is CD320 p.Arg254Ter (c.760C>T) pathogenic?

CD320 p.Arg254Ter (c.760C>T) is classified Uncertain significance in CD320 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-12). Ultra-rare (popmax 0.0178%, eas); Associated with methylmalonic acidemia due to transcobalamin receptor defect.

What condition is associated with CD320 p.Arg254Ter (c.760C>T)?

CD320 p.Arg254Ter (c.760C>T) is associated with methylmalonic acidemia due to transcobalamin receptor defect (ClinVar).

How common is CD320 p.Arg254Ter (c.760C>T) in the general population?

CD320 p.Arg254Ter (c.760C>T) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

CD320 p.Arg254Ter

c.760C>T · rs750760449 · VCV1063339

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Conditions

methylmalonic acidemia due to transcobalamin receptor defect

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	escapes	premature termination codon in the last exon (5 of 5) — the truncated protein is likely expressed. PVS1 input, not an applied code
REVEL	0.031	moderately benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.67 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.2	GERP -1.4, phastCons 0.001
Overall
CADD	35.0	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 0.0178% East Asian · 8/44,882 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00223% 36/1,614,016 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,610
African / African-American	0.00533%	18,757
Finnishnot grpmax-eligible	0.00469%	21,313
Remaining individualsnot grpmax-eligible	0.0032%	31,252
European (non-Finnish)	0.00161%	62,104

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: CD320
Protein: p.Arg254Ter
Coding: c.760C>T
MANE Select: NM_016579
dbSNP: rs750760449
Type: single nucleotide variant
Location: chr19:8302552 (GRCh38)
Gene constraint: LOEUF 1.488 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.61 · 6 PDB

Full CD320 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

methylmalonic acidemia due to transcobalamin receptor defect — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CD320 p.Arg254Gln Uncertain significance ★★ ⚠ same residue
CD320 p.Arg254= Uncertain significance ★ same residue
CD320 p.Arg129Leu Uncertain significance ★★ ⚠ same condition
CD320 p.Arg138Ser Uncertain significance ★★ ⚠ same condition
CD320 p.Arg258His Uncertain significance ★★ ⚠ same condition
CD320 p.Asn170Ser Uncertain significance ★★ ⚠ same condition
CD320 p.Asp143Asn Uncertain significance ★★ ⚠ same condition
CD320 p.Asp160Asn 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/cd320-p-arg254ter (accessed [today's date]).

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