Is CD320 p.Pro93Ser (c.277C>T) pathogenic?

CD320 p.Pro93Ser (c.277C>T) is classified Uncertain significance in CD320 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-25). AlphaMissense: likely benign (0.1592); Ultra-rare (popmax 0.0169%, mid); Associated with methylmalonic acidemia due to transcobalamin receptor defect.

What condition is associated with CD320 p.Pro93Ser (c.277C>T)?

CD320 p.Pro93Ser (c.277C>T) is associated with methylmalonic acidemia due to transcobalamin receptor defect (ClinVar).

How common is CD320 p.Pro93Ser (c.277C>T) in the general population?

CD320 p.Pro93Ser (c.277C>T) is ultra-rare (popmax 0.0169%, mid) (gnomAD).

What do computational predictors say about CD320 p.Pro93Ser (c.277C>T)?

AlphaMissense predicts likely benign (score 0.1592) — an in-silico prediction, not a clinical call.

CD320 p.Pro93Ser

c.277C>T · rs377236965 · VCV429626

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1592 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

methylmalonic acidemia due to transcobalamin receptor defect

Computational evidence

Protein change
AlphaMissense	0.1592	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -5.48	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 5,824 bp · p 0.57 · regional, not allelic
Overall
CADD	16.93	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 0.0169% Middle Eastern · 1/5,930 alleles

Filtering AF 0.00783% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00732%

Overall 0.00764% 116/1,517,600 alleles · ultra-rare exomes 105/1,365,374 · genomes 11/152,226 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0169%	5,930
Remaining individualsnot grpmax-eligible	0.0119%	8,431
European (non-Finnish)	0.00932%	10,727
African / African-American	0.00276%	36,278
South Asian	0.0024%	41,749

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.Pro93Ser
Coding: c.277C>T
MANE Select: NM_016579
dbSNP: rs377236965
Type: single nucleotide variant
Location: chr19:8304080 (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.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
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-pro93ser (accessed [today's date]).

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