Is CUBN p.Phe2513Leu (c.7539C>A) pathogenic?

CUBN p.Phe2513Leu (c.7539C>A) is classified Uncertain significance in CUBN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely pathogenic (0.6274); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CUBN p.Phe2513Leu (c.7539C>A)?

CUBN p.Phe2513Leu (c.7539C>A) is associated with Inborn genetic diseases (ClinVar).

How common is CUBN p.Phe2513Leu (c.7539C>A) in the general population?

CUBN p.Phe2513Leu (c.7539C>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CUBN p.Phe2513Leu (c.7539C>A)?

AlphaMissense predicts likely pathogenic (score 0.6274) — an in-silico prediction, not a clinical call.

CUBN p.Phe2513Leu

c.7539C>A · VCV4616767

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6274 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6274	likely pathogenic
REVEL	0.109	moderately benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.7, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 84 kb · p 0.074 · regional, not allelic
Overall
CADD	17.64	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 8.48e-05% European (non-Finnish) · 1/1,179,782 alleles

Overall 6.85e-05% 1/1,459,628 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: CUBN
Protein: p.Phe2513Leu
Coding: c.7539C>A
MANE Select: NM_001081
Type: single nucleotide variant
Location: chr10:16907674 (GRCh38)
Gene constraint: LOEUF 0.756 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2513: a disulfide bond; a UniProt-annotated variant site (in prochob); the cub 18 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CUBN p.Arg2444Ter Pathogenic ★★ same condition
CUBN p.Ala1501Glu Uncertain significance ★★ same condition
CUBN p.Ala2086Thr Uncertain significance ★★ same condition
CUBN p.Ala238Val Uncertain significance ★★ ⚠ same condition
CUBN p.Arg1268Cys Uncertain significance ★★ ⚠ same condition
CUBN p.Arg1345Trp Uncertain significance ★★ ⚠ same condition
CUBN p.Arg1636Trp Uncertain significance ★★ ⚠ same condition
CUBN p.Arg1695His Uncertain significance ★★ 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/cubn-p-phe2513leu (accessed [today's date]).

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