Is CD320 p.Glu257Lys (c.769G>A) pathogenic?

CD320 p.Glu257Lys (c.769G>A) is classified Benign/Likely benign in CD320 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-21). AlphaMissense: likely benign (0.2126); Low-frequency (popmax 4.35%, afr); Associated with methylmalonic acidemia due to transcobalamin receptor defect.

What condition is associated with CD320 p.Glu257Lys (c.769G>A)?

CD320 p.Glu257Lys (c.769G>A) is associated with methylmalonic acidemia due to transcobalamin receptor defect (ClinVar).

How common is CD320 p.Glu257Lys (c.769G>A) in the general population?

CD320 p.Glu257Lys (c.769G>A) is low-frequency (popmax 4.35%, afr) (gnomAD).

What do computational predictors say about CD320 p.Glu257Lys (c.769G>A)?

AlphaMissense predicts likely benign (score 0.2126) — an in-silico prediction, not a clinical call.

CD320 p.Glu257Lys

c.769G>A · rs2232786 · VCV382056

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2126 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.35%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

methylmalonic acidemia due to transcobalamin receptor defect

Computational evidence

Protein change
AlphaMissense	0.2126	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -3.48	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 0.3	GERP 0.81, phastCons 0.002
Regional constraint	o/e 1.03	unconstrained · MANE · 5,824 bp · p 0.57 · regional, not allelic
Overall
CADD	11.15	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 4.35% African / African-American · 3,267/75,032 alleles

Filtering AF 4.23% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.18%

Overall 0.249% 4,017/1,614,076 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.35%	23
Middle Eastern	0.478%	209
Admixed American	0.383%	261
Remaining individualsnot grpmax-eligible	0.37%	271
South Asian	0.0209%	4,794
European (non-Finnish)	0.0203%	4,917
East Asian	0.00223%	44,880

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.Glu257Lys
Coding: c.769G>A
MANE Select: NM_016579
dbSNP: rs2232786
Type: single nucleotide variant
Location: chr19:8302543 (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-glu257lys (accessed [today's date]).

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