Is CD46 p.Arg218Pro (c.653G>C) pathogenic?

CD46 p.Arg218Pro (c.653G>C) is classified Uncertain significance in CD46 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-13). AlphaMissense: ambiguous (0.3552); Absent from gnomAD v4.1.

How common is CD46 p.Arg218Pro (c.653G>C) in the general population?

CD46 p.Arg218Pro (c.653G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CD46 p.Arg218Pro (c.653G>C)?

AlphaMissense predicts ambiguous (score 0.3552) — an in-silico prediction, not a clinical call.

CD46 p.Arg218Pro

c.653G>C · rs770322216 · VCV2702679

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3552 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3552	ambiguous
REVEL	0.074	moderately benign-leaning
SaProt	LLR -4.10	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.15	GERP -2.3
Regional constraint	o/e 0.88	unconstrained · MANE · 38 kb · p 0.012 · regional, not allelic
Overall
CADD	10.86	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.Arg218Pro
Coding: c.653G>C
MANE Select: NM_172351
dbSNP: rs770322216
Type: single nucleotide variant
Location: chr1:207761426 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 7 PDB
Residue 218: a disulfide bond; the sushi 3 domain; a β-strand

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

Similar variants

CD46 p.Arg218His Uncertain significance ★★ ⚠ same residue
CD46 p.Arg218Cys Uncertain significance ★ ⚠ same residue
CD46 p.Arg218Leu Uncertain significance ★ ⚠ same residue
CD46 c.1082+2T>A Pathogenic ★★ same type
CD46 c.286+1G>C Pathogenic/Likely pathogenic ★★ same type
CD46 c.286+2T>G Pathogenic/Likely pathogenic ★★ same type
CD46 c.287-2A>G Pathogenic/Likely pathogenic ★★ same type
CD46 p.Arg229Ter Pathogenic/Likely 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-arg218pro (accessed [today's date]).

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