Is CD46 p.Pro112Leu (c.335C>T) pathogenic?

CD46 p.Pro112Leu (c.335C>T) is classified Uncertain significance in CD46 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-05). AlphaMissense: likely benign (0.0887); Very rare (popmax 0.00401%, afr).

How common is CD46 p.Pro112Leu (c.335C>T) in the general population?

CD46 p.Pro112Leu (c.335C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about CD46 p.Pro112Leu (c.335C>T)?

AlphaMissense predicts likely benign (score 0.0887) — an in-silico prediction, not a clinical call.

CD46 p.Pro112Leu

c.335C>T · rs1420887927 · VCV1374983

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0887 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0887	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -3.48	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 -7.8	GERP -3
Regional constraint	o/e 0.88	unconstrained · MANE · 38 kb · p 0.012 · regional, not allelic
Overall
CADD	0.001	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 0.00401% African / African-American · 3/74,856 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,611,798 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.Pro112Leu
Coding: c.335C>T
MANE Select: NM_172351
dbSNP: rs1420887927
Type: single nucleotide variant
Location: chr1:207757588 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 82.38 · 7 PDB
Residue 112: a disulfide bond; the sushi 2 domain; a β-strand

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

Similar variants

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
CD46 p.Phe242Cys Pathogenic/Likely pathogenic ★★ same type
CD46 p.Trp276Ter 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-pro112leu (accessed [today's date]).

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