Is CD46 p.Cys127Phe (c.380G>T) pathogenic?

CD46 p.Cys127Phe (c.380G>T) is classified Likely pathogenic in CD46 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-09). AlphaMissense: likely pathogenic (0.9925); Very rare (popmax 8.6e-05%, nfe); Associated with atypical hemolytic-uremic syndrome with MCP/CD46 anomaly.

What condition is associated with CD46 p.Cys127Phe (c.380G>T)?

CD46 p.Cys127Phe (c.380G>T) is associated with atypical hemolytic-uremic syndrome with MCP/CD46 anomaly (ClinVar).

How common is CD46 p.Cys127Phe (c.380G>T) in the general population?

CD46 p.Cys127Phe (c.380G>T) is very rare (popmax 8.6e-05%, nfe) (gnomAD).

What do computational predictors say about CD46 p.Cys127Phe (c.380G>T)?

AlphaMissense predicts likely pathogenic (score 0.9925) — an in-silico prediction, not a clinical call.

CD46 p.Cys127Phe

c.380G>T · VCV4852331

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9925 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.6e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atypical hemolytic-uremic syndrome with MCP/CD46 anomaly

Computational evidence

Protein change
AlphaMissense	0.9925	likely pathogenic ✓ concordant with ClinVar · top 3% in CD46
REVEL	0.762	pathogenic-leaning
SaProt	LLR -13.32	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 38 kb · p 0.012 · regional, not allelic
Overall
CADD	25.3	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 8.6e-05% European (non-Finnish) · 1/1,162,302 alleles

Overall 6.94e-05% 1/1,440,344 alleles · very rare

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.Cys127Phe
Coding: c.380G>T
MANE Select: NM_172351
Type: single nucleotide variant
Location: chr1:207757633 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 7 PDB
Residue 127: a disulfide bond; the sushi 2 domain; a β-strand

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

Disease context

atypical hemolytic-uremic syndrome with MCP/CD46 anomaly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CD46 c.1082+2T>A Pathogenic ★★ same condition
CD46 c.286+2T>G Pathogenic/Likely pathogenic ★★ same condition
CD46 c.287-2A>G Pathogenic/Likely pathogenic ★★ same condition
CD46 p.Arg229Ter Pathogenic/Likely pathogenic ★★ same condition
CD46 p.Arg59Ter Pathogenic/Likely pathogenic ★★ same condition
CD46 p.Trp276Ter Pathogenic ★★ same condition
CD46 c.857-124T>A Uncertain significance ★★ same condition
CD46 c.*52G>A 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/cd46-p-cys127phe (accessed [today's date]).

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