Is CD320 p.Arg138Ser (c.412C>A) pathogenic?

CD320 p.Arg138Ser (c.412C>A) is classified Uncertain significance in CD320 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-24). AlphaMissense: ambiguous (0.4174); Very rare (popmax 0.00658%, nfe); Associated with methylmalonic acidemia due to transcobalamin receptor defect.

What condition is associated with CD320 p.Arg138Ser (c.412C>A)?

CD320 p.Arg138Ser (c.412C>A) is associated with methylmalonic acidemia due to transcobalamin receptor defect (ClinVar).

How common is CD320 p.Arg138Ser (c.412C>A) in the general population?

CD320 p.Arg138Ser (c.412C>A) is very rare (popmax 0.00658%, nfe) (gnomAD).

What do computational predictors say about CD320 p.Arg138Ser (c.412C>A)?

AlphaMissense predicts ambiguous (score 0.4174) — an in-silico prediction, not a clinical call.

CD320 p.Arg138Ser

c.412C>A · rs201166605 · VCV1054168

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4174 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00658%, nfe)

Conditions

methylmalonic acidemia due to transcobalamin receptor defect

Computational evidence

Protein change
AlphaMissense	0.4174	ambiguous
REVEL	0.319	indeterminate
SaProt	LLR -7.21	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.9	GERP -0.21, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 5,824 bp · p 0.57 · regional, not allelic
Overall
CADD	19.04	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00658% European (non-Finnish) · 77/1,170,814 alleles

Filtering AF 0.00534% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00493%

Overall 0.00872% 139/1,594,194 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0786%	1,273
Remaining individualsnot grpmax-eligible	0.013%	7,718
Ashkenazi Jewishnot grpmax-eligible	0.00685%	14,600
European (non-Finnish)grpmax	0.00658%	15,205
Admixed American	0.00527%	18,982

Finnish 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: CD320
Protein: p.Arg138Ser
Coding: c.412C>A
MANE Select: NM_016579
dbSNP: rs201166605
Type: single nucleotide variant
Location: chr19:8303945 (GRCh38)
Gene constraint: LOEUF 1.488 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.61 · 6 PDB
Residue 138: a disulfide bond; a β-strand; the ldl-receptor class a 2 domain

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.Arg138Pro Uncertain significance ★ ⚠ same residue
CD320 p.Arg129Leu 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-arg138ser (accessed [today's date]).

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