Is CD320 p.Thr140Met (c.419C>T) pathogenic?

CD320 p.Thr140Met (c.419C>T) is classified Uncertain significance in CD320 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-14). AlphaMissense: likely benign (0.1269); Very rare (popmax 0.00113%, sas).

How common is CD320 p.Thr140Met (c.419C>T) in the general population?

CD320 p.Thr140Met (c.419C>T) is very rare (popmax 0.00113%, sas) (gnomAD).

What do computational predictors say about CD320 p.Thr140Met (c.419C>T)?

AlphaMissense predicts likely benign (score 0.1269) — an in-silico prediction, not a clinical call.

CD320 p.Thr140Met

c.419C>T · VCV4222856

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1269 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00113%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1269	likely benign
REVEL	0.467	indeterminate
SaProt	LLR -6.42	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.61 · evaluated, not missing
Constraint at this position
Conservation	phyloP -2.7	GERP -3.7
Regional constraint	o/e 1.03	unconstrained · MANE · 5,824 bp · p 0.57 · regional, not allelic
Overall
CADD	0.094	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 0.00113% South Asian · 1/88,378 alleles

Filtering AF 0.000184% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000438% 7/1,597,992 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00113%	88,378
European (non-Finnish)	0.000512%	195,455

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.Thr140Met
Coding: c.419C>T
MANE Select: NM_016579
Type: single nucleotide variant
Location: chr19:8303938 (GRCh38)
Gene constraint: LOEUF 1.488 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.61 · 6 PDB
Residue 140: 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

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-thr140met (accessed [today's date]).

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