Is CD46 p.Ile203Phe (c.607A>T) pathogenic?

CD46 p.Ile203Phe (c.607A>T) is classified Uncertain significance in CD46 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-14). AlphaMissense: ambiguous (0.4185); Absent from gnomAD v4.1; Associated with atypical hemolytic-uremic syndrome with MCP/CD46 anomaly.

What condition is associated with CD46 p.Ile203Phe (c.607A>T)?

CD46 p.Ile203Phe (c.607A>T) is associated with atypical hemolytic-uremic syndrome with MCP/CD46 anomaly (ClinVar).

How common is CD46 p.Ile203Phe (c.607A>T) in the general population?

CD46 p.Ile203Phe (c.607A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CD46 p.Ile203Phe (c.607A>T)?

AlphaMissense predicts ambiguous (score 0.4185) — an in-silico prediction, not a clinical call.

CD46 p.Ile203Phe

c.607A>T · VCV4540432

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4185 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

atypical hemolytic-uremic syndrome with MCP/CD46 anomaly

Computational evidence

Protein change
AlphaMissense	0.4185	ambiguous
REVEL	0.202	benign-leaning
SaProt	LLR -10.36	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.7	GERP -3.4
Regional constraint	o/e 0.88	unconstrained · MANE · 38 kb · p 0.012 · regional, not allelic
Overall
CADD	5.551	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CD46
Protein: p.Ile203Phe
Coding: c.607A>T
MANE Select: NM_172351
Type: single nucleotide variant
Location: chr1:207761380 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 7 PDB
Residue 203: a disulfide bond; the sushi 3 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 p.Ile203Thr Uncertain significance ★ ⚠ same residue
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

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-ile203phe (accessed [today's date]).

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