Is CD46 p.Pro164Gln (c.491C>A) pathogenic?

CD46 p.Pro164Gln (c.491C>A) is classified Uncertain significance in CD46 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-15). AlphaMissense: likely benign (0.2828); Very rare (popmax 0.00196%, nfe); Associated with atypical hemolytic-uremic syndrome with MCP/CD46 anomaly.

What condition is associated with CD46 p.Pro164Gln (c.491C>A)?

CD46 p.Pro164Gln (c.491C>A) is associated with atypical hemolytic-uremic syndrome with MCP/CD46 anomaly (ClinVar).

How common is CD46 p.Pro164Gln (c.491C>A) in the general population?

CD46 p.Pro164Gln (c.491C>A) is very rare (popmax 0.00196%, nfe) (gnomAD).

What do computational predictors say about CD46 p.Pro164Gln (c.491C>A)?

AlphaMissense predicts likely benign (score 0.2828) — an in-silico prediction, not a clinical call.

CD46 p.Pro164Gln

c.491C>A · rs746757476 · VCV1417252

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2828 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00196%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

atypical hemolytic-uremic syndrome with MCP/CD46 anomaly

Computational evidence

Protein change
AlphaMissense	0.2828	likely benign
REVEL	0.297	indeterminate
SaProt	LLR -10.85	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
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	22.0	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 0.00196% European (non-Finnish) · 23/1,173,982 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00109%

Overall 0.00149% 24/1,606,916 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00196%	51,043
Finnishnot grpmax-eligible	0.00156%	63,912

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.Pro164Gln
Coding: c.491C>A
MANE Select: NM_172351
dbSNP: rs746757476
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: a disulfide bond; the sushi 3 domain; an α-helix

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.Pro164Ala Uncertain significance ★ ⚠ same residue
CD46 p.Pro164Arg Uncertain significance ★ ⚠ same residue
CD46 p.Pro164Ser 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

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-pro164gln (accessed [today's date]).

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