Is CD46 p.Pro164Arg (c.491C>G) pathogenic?

CD46 p.Pro164Arg (c.491C>G) is classified Uncertain significance in CD46 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). AlphaMissense: likely benign (0.2448); Very rare (popmax 6.22e-05%).

How common is CD46 p.Pro164Arg (c.491C>G) in the general population?

CD46 p.Pro164Arg (c.491C>G) is very rare (popmax 6.22e-05%) (gnomAD).

What do computational predictors say about CD46 p.Pro164Arg (c.491C>G)?

AlphaMissense predicts likely benign (score 0.2448) — an in-silico prediction, not a clinical call.

CD46 p.Pro164Arg

c.491C>G · VCV4650639

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2448 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.22e-05%)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2448	likely benign
REVEL	0.241	benign-leaning
SaProt	LLR -10.37	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.13	GERP 1.7
Regional constraint	o/e 0.88	unconstrained · MANE · 38 kb · p 0.012 · regional, not allelic
Overall
CADD	23.5	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 6.22e-05%

Overall 6.22e-05% 1/1,606,916 alleles · very rare exomes 0/1,454,924 · genomes 1/151,992 · joint denominator

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.Pro164Arg
Coding: c.491C>G
MANE Select: NM_172351
Type: single nucleotide variant
Location: chr1:207761264 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 7 PDB
Residue 164: the sushi 3 domain; an α-helix

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

Similar variants

CD46 p.Pro164Gln Uncertain significance ★★ ⚠ same residue
CD46 p.Pro164Ala Uncertain significance ★ ⚠ same residue
CD46 p.Pro164Ser 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-pro164arg (accessed [today's date]).

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