Is CD46 p.Thr375fs (c.1123_*4del) pathogenic?

CD46 p.Thr375fs (c.11234del) is classified Uncertain significance in CD46 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-07-10). Very rare (popmax 0.0066%, sas).

How common is CD46 p.Thr375fs (c.1123_*4del) in the general population?

CD46 p.Thr375fs (c.1123_*4del) is very rare (popmax 0.0066%, sas) (gnomAD).

CD46 p.Thr375fs

c.1123_*4del · VCV4930887

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0066%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.2	GERP 0.16, phastCons 0.97

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0066% South Asian · 6/90,850 alleles

Filtering AF 0.00287% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00196%

Overall 0.000375% 6/1,600,228 alleles · very rare exomes 6/1,447,868 · genomes 0/152,360 · joint denominator

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: CD46
Protein: p.Thr375fs
Coding: c.1123_*4del
MANE Select: NM_172351
Type: Deletion
Location: chr1:207790293 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 7 PDB

Full CD46 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD46 p.Ala296fs Pathogenic/Likely pathogenic ★★ same type
CD46 p.Asp271_Ser272del Pathogenic/Likely pathogenic ★★ same type
CD46 p.Lys51fs Pathogenic/Likely pathogenic ★★ same type
CD46 c.286+27del Benign/Likely benign ★★ same type
CD46 c.856+2del Likely pathogenic ★ same type
CD46 p.Asp257fs Pathogenic ★ same type
CD46 p.Gln238fs Likely pathogenic ★ same type
CD46 p.Glu137fs Pathogenic ★ 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/cd46-p-thr375fs (accessed [today's date]).

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