Is CD46 p.His84Arg (c.251A>G) pathogenic?

CD46 p.His84Arg (c.251A>G) is classified Uncertain significance in CD46 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-01). AlphaMissense: likely benign (0.1328); Very rare (popmax 0.000339%, nfe).

How common is CD46 p.His84Arg (c.251A>G) in the general population?

CD46 p.His84Arg (c.251A>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about CD46 p.His84Arg (c.251A>G)?

AlphaMissense predicts likely benign (score 0.1328) — an in-silico prediction, not a clinical call.

CD46 p.His84Arg

c.251A>G · rs1047780483 · VCV2799169

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1328 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1328	likely benign
REVEL	0.18	moderately benign-leaning
SaProt	LLR -3.31	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -2.5
Regional constraint	o/e 0.88	unconstrained · MANE · 38 kb · p 0.012 · regional, not allelic
Overall
CADD	13.87	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,968 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,618 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.His84Arg
Coding: c.251A>G
MANE Select: NM_172351
dbSNP: rs1047780483
Type: single nucleotide variant
Location: chr1:207757167 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 7 PDB
Residue 84: a disulfide bond; the sushi 1 domain; a β-strand

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

Similar variants

CD46 p.His84Leu Uncertain significance ★ ⚠ same residue
CD46 p.His84Pro 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
CD46 p.Arg59Ter 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-his84arg (accessed [today's date]).

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