Is CD46 p.Pro195Ser (c.583C>T) pathogenic?

CD46 p.Pro195Ser (c.583C>T) is classified Uncertain significance in CD46 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-02). AlphaMissense: likely benign (0.1228); Ultra-rare (popmax 0.0178%, eas); Associated with atypical hemolytic-uremic syndrome.

What condition is associated with CD46 p.Pro195Ser (c.583C>T)?

CD46 p.Pro195Ser (c.583C>T) is associated with atypical hemolytic-uremic syndrome (ClinVar).

How common is CD46 p.Pro195Ser (c.583C>T) in the general population?

CD46 p.Pro195Ser (c.583C>T) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

How is Atypical hemolytic uremic syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CD46 p.Pro195Ser (c.583C>T)?

AlphaMissense predicts likely benign (score 0.1228) — an in-silico prediction, not a clinical call.

CD46 p.Pro195Ser

c.583C>T · VCV4291157

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1228 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.1228	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -5.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.41 · evaluated, not missing
Constraint at this position
Conservation	phyloP -6.7	GERP -3.4
Regional constraint	o/e 0.88	unconstrained · MANE · 38 kb · p 0.012 · regional, not allelic
Overall
CADD	0.309	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 0.0178% East Asian · 8/44,860 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.000496% 8/1,613,594 alleles · ultra-rare exomes 8/1,461,262 · genomes 0/152,332 · 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.Pro195Ser
Coding: c.583C>T
MANE Select: NM_172351
Type: single nucleotide variant
Location: chr1:207761356 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 7 PDB
Residue 195: 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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Atypical hemolytic uremic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

CD46 p.Pro195Ala Uncertain significance ★ ⚠ same residue
CD46 c.1082+2T>A Pathogenic ★★ same condition
CD46 c.286+1G>C Pathogenic/Likely 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.Phe242Cys 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-pro195ser (accessed [today's date]).

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