Is CD46 p.Ser240Pro (c.718T>C) pathogenic?

CD46 p.Ser240Pro (c.718T>C) is classified Conflicting classifications of pathogenicity in CD46 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-06). AlphaMissense: likely pathogenic (0.8979); Very rare (popmax 0.0011%, sas); Associated with CD46-related disorders.

What condition is associated with CD46 p.Ser240Pro (c.718T>C)?

CD46 p.Ser240Pro (c.718T>C) is associated with CD46-related disorders, atypical hemolytic-uremic syndrome with MCP/CD46 anomaly, atypical hemolytic-uremic syndrome (ClinVar).

How common is CD46 p.Ser240Pro (c.718T>C) in the general population?

CD46 p.Ser240Pro (c.718T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CD46 p.Ser240Pro (c.718T>C)?

AlphaMissense predicts likely pathogenic (score 0.8979) — an in-silico prediction, not a clinical call.

CD46 p.Ser240Pro

c.718T>C · rs121909589 · VCV17046

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.8979 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CD46-related disorders

Computational evidence

Protein change
AlphaMissense	0.8979	likely pathogenic
REVEL	0.335	indeterminate
SaProt	LLR -13.54	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -3.7
Regional constraint	o/e 0.88	unconstrained · MANE · 38 kb · p 0.012 · regional, not allelic
Overall
CADD	13.29	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 0.0011% South Asian · 1/91,082 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,613,692 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,082
European (non-Finnish)	0.000509%	196,627

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.Ser240Pro
Coding: c.718T>C
MANE Select: NM_172351
dbSNP: rs121909589
Type: single nucleotide variant
Location: chr1:207767057 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 7 PDB
Residue 240: a β-strand; a disulfide bond; a UniProt-annotated variant site (in ahus2; no change in cell surface expression but reduced activity); the sushi 4 domain

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

Disease context

CD46-related disorders

Also linked: atypical hemolytic-uremic syndrome with MCP/CD46 anomaly atypical hemolytic-uremic syndrome

Similar variants

CD46 p.Ser240Ala 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-ser240pro (accessed [today's date]).

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