Is CD46 p.Cys64Phe (c.191G>T) pathogenic?

CD46 p.Cys64Phe (c.191G>T) is classified Conflicting classifications of pathogenicity in CD46 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-10-02). AlphaMissense: likely pathogenic (0.9743); Very rare (popmax 0.00153%, nfe); Associated with atypical hemolytic-uremic syndrome with MCP/CD46 anomaly.

How common is CD46 p.Cys64Phe (c.191G>T) in the general population?

CD46 p.Cys64Phe (c.191G>T) is very rare (popmax 0.00153%, nfe) (gnomAD).

What do computational predictors say about CD46 p.Cys64Phe (c.191G>T)?

AlphaMissense predicts likely pathogenic (score 0.9743) — an in-silico prediction, not a clinical call.

CD46 p.Cys64Phe

Q: What condition is associated with CD46 p.Cys64Phe (c.191G>T)?

CD46 p.Cys64Phe (c.191G>T) is associated with atypical hemolytic-uremic syndrome with MCP/CD46 anomaly, atypical hemolytic-uremic syndrome (ClinVar).

c.191G>T · rs1655633353 · VCV1698741

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9743 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atypical hemolytic-uremic syndrome with MCP/CD46 anomaly

Computational evidence

Protein change
AlphaMissense	0.9743	likely pathogenic · top 6% in CD46
REVEL	0.696	pathogenic-leaning
SaProt	LLR -14.34	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 5.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 38 kb · p 0.012 · regional, not allelic
Overall
CADD	23.9	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 0.00153% European (non-Finnish) · 18/1,179,742 alleles

Filtering AF 0.000954% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00123% 18/1,461,536 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.Cys64Phe
Coding: c.191G>T
MANE Select: NM_172351
dbSNP: rs1655633353
Type: single nucleotide variant
Location: chr1:207757107 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 7 PDB
Residue 64: a disulfide bond; the sushi 1 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

Also linked: atypical hemolytic-uremic syndrome

Similar variants

CD46 p.Cys64Tyr Uncertain significance ★★ ⚠ same residue
CD46 c.1082+2T>A Pathogenic ★★ same condition
CD46 c.286+1G>C Pathogenic/Likely 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.Phe242Cys Pathogenic/Likely pathogenic ★★ 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-cys64phe (accessed [today's date]).

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