Is CD320 p.Arg129Leu (c.386G>T) pathogenic?

CD320 p.Arg129Leu (c.386G>T) is classified Uncertain significance in CD320 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-24). AlphaMissense: likely benign (0.1681); Ultra-rare (popmax 0.0374%, nfe); Associated with methylmalonic acidemia due to transcobalamin receptor defect.

What condition is associated with CD320 p.Arg129Leu (c.386G>T)?

CD320 p.Arg129Leu (c.386G>T) is associated with methylmalonic acidemia due to transcobalamin receptor defect (ClinVar).

How common is CD320 p.Arg129Leu (c.386G>T) in the general population?

CD320 p.Arg129Leu (c.386G>T) is ultra-rare (popmax 0.0374%, nfe) (gnomAD).

What do computational predictors say about CD320 p.Arg129Leu (c.386G>T)?

AlphaMissense predicts likely benign (score 0.1681) — an in-silico prediction, not a clinical call.

CD320 p.Arg129Leu

c.386G>T · rs139064611 · VCV1416159

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1681 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0374%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

methylmalonic acidemia due to transcobalamin receptor defect

Computational evidence

Protein change
AlphaMissense	0.1681	likely benign
REVEL	0.233	benign-leaning
SaProt	LLR -6.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.26	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -7.5	GERP -3.7
Regional constraint	o/e 1.03	unconstrained · MANE · 5,824 bp · p 0.57 · regional, not allelic
Overall
CADD	0.085	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 0.0374% European (non-Finnish) · 435/1,164,088 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0333%

Overall 0.0286% 453/1,581,698 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0374%	2,676
Remaining individualsnot grpmax-eligible	0.0163%	6,130
Admixed American	0.00547%	18,265
Finnishnot grpmax-eligible	0.00487%	20,515
African / African-American	0.00269%	37,147

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.Arg129Leu
Coding: c.386G>T
MANE Select: NM_016579
dbSNP: rs139064611
Type: single nucleotide variant
Location: chr19:8303971 (GRCh38)
Gene constraint: LOEUF 1.488 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.61 · 6 PDB
Residue 129: a UniProt-annotated variant site (in matr; uncertain significance)

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.Arg129His Uncertain significance ★ ⚠ same residue
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
CD320 p.Gly166Val 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-arg129leu (accessed [today's date]).

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