Is CD320 p.Leu133Val (c.397C>G) pathogenic?

CD320 p.Leu133Val (c.397C>G) is classified Uncertain significance in CD320 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-24). AlphaMissense: likely benign (0.0999); Ultra-rare (popmax 0.0206%, sas).

How common is CD320 p.Leu133Val (c.397C>G) in the general population?

CD320 p.Leu133Val (c.397C>G) is ultra-rare (popmax 0.0206%, sas) (gnomAD).

What do computational predictors say about CD320 p.Leu133Val (c.397C>G)?

AlphaMissense predicts likely benign (score 0.0999) — an in-silico prediction, not a clinical call.

CD320 p.Leu133Val

c.397C>G · VCV4650597

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0999 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0206%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0999	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -7.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.22	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 3.9	GERP 0.84, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 5,824 bp · p 0.57 · regional, not allelic
Overall
CADD	16.83	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 0.0206% South Asian · 18/87,188 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.011%

Overall 0.0012% 19/1,586,196 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0206%	4,844
Remaining individualsnot grpmax-eligible	0.00163%	61,454

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.Leu133Val
Coding: c.397C>G
MANE Select: NM_016579
Type: single nucleotide variant
Location: chr19:8303960 (GRCh38)
Gene constraint: LOEUF 1.488 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.61 · 6 PDB
Residue 133: a disulfide bond; an α-helix; the ldl-receptor class a 2 domain

Full CD320 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD320 p.Arg129Leu Uncertain significance ★★ ⚠ same type
CD320 p.Arg138Ser Uncertain significance ★★ ⚠ same type
CD320 p.Arg254Gln Uncertain significance ★★ ⚠ same type
CD320 p.Arg258His Uncertain significance ★★ ⚠ same type
CD320 p.Asn170Ser Uncertain significance ★★ ⚠ same type
CD320 p.Asp143Asn Uncertain significance ★★ ⚠ same type
CD320 p.Asp160Asn Uncertain significance ★★ ⚠ same type
CD320 p.Gly166Val Uncertain significance ★★ ⚠ same type

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-leu133val (accessed [today's date]).

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