Is CD320 p.Ala219= (c.657C>T) pathogenic?

CD320 p.Ala219= (c.657C>T) is classified Likely benign in CD320 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-17). Ultra-rare (popmax 0.012%, afr); Associated with methylmalonic acidemia due to transcobalamin receptor defect.

What condition is associated with CD320 p.Ala219= (c.657C>T)?

CD320 p.Ala219= (c.657C>T) is associated with methylmalonic acidemia due to transcobalamin receptor defect (ClinVar).

How common is CD320 p.Ala219= (c.657C>T) in the general population?

CD320 p.Ala219= (c.657C>T) is ultra-rare (popmax 0.012%, afr) (gnomAD).

CD320 p.Ala219=

c.657C>T · rs368089898 · VCV1091710

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

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.
REVEL	0.031	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.5	GERP -2.9
Overall
CADD	0.376	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% African / African-American · 9/75,020 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.00291% 47/1,614,108 alleles · ultra-rare exomes 40/1,461,888 · genomes 7/152,220 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,336
South Asian	0.00329%	30,362
Remaining individualsnot grpmax-eligible	0.0032%	31,253
European (non-Finnish)	0.00263%	38,064
East Asian	0.00223%	44,866
Admixed American	0.00167%	60,012

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.Ala219=
Coding: c.657C>T
MANE Select: NM_016579
dbSNP: rs368089898
Type: single nucleotide variant
Location: chr19:8302826 (GRCh38)
Gene constraint: LOEUF 1.488 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.61 · 6 PDB
Residue 219: the 'disordered' region

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.Ala219Ser Uncertain significance ★ ⚠ same residue
CD320 p.Arg129Leu Uncertain significance ★★ ⚠ same condition
CD320 p.Arg138Ser Uncertain significance ★★ same condition
CD320 p.Arg254Gln 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-ala219 (accessed [today's date]).

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