Is BCAN p.Leu840Phe (c.2518C>T) pathogenic?

BCAN p.Leu840Phe (c.2518C>T) is classified Uncertain significance in BCAN (ClinVar, Single submitter, 2 submitters; last evaluated 2024-08-05). AlphaMissense: likely benign (0.1999); Ultra-rare (popmax 0.0313%, nfe).

How common is BCAN p.Leu840Phe (c.2518C>T) in the general population?

BCAN p.Leu840Phe (c.2518C>T) is ultra-rare (popmax 0.0313%, nfe) (gnomAD).

What do computational predictors say about BCAN p.Leu840Phe (c.2518C>T)?

AlphaMissense predicts likely benign (score 0.1999) — an in-silico prediction, not a clinical call.

BCAN p.Leu840Phe

c.2518C>T · rs200282065 · VCV623463

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1999 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0313%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1999	likely benign
REVEL	0.289	benign-leaning
SaProt	LLR -10.49	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.7	GERP -0.18, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.11 · regional, not allelic
Overall
CADD	26.5	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 0.0313% European (non-Finnish) · 369/1,180,062 alleles

Filtering AF 0.0286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0276%

Overall 0.0239% 386/1,614,028 alleles · ultra-rare exomes 345/1,461,770 · genomes 41/152,258 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0313%	3,198
Remaining individualsnot grpmax-eligible	0.0128%	7,811
Finnishnot grpmax-eligible	0.00782%	12,784
Admixed American	0.00333%	30,008
African / African-American	0.00267%	37,472

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: BCAN
Protein: p.Leu840Phe
Coding: c.2518C>T
MANE Select: NM_021948
dbSNP: rs200282065
Type: single nucleotide variant
Location: chr1:156658623 (GRCh38)
Gene constraint: LOEUF 0.695 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.06
Residue 840: the sushi domain

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

Similar variants

BCAN p.Arg105Gly Benign ★★ same type
BCAN p.Ala10Pro Uncertain significance ★ ⚠ same type
BCAN p.Ala112Thr Uncertain significance ★ ⚠ same type
BCAN p.Ala166Val Uncertain significance ★ ⚠ same type
BCAN p.Ala169Thr Uncertain significance ★ ⚠ same type
BCAN p.Ala2Thr Uncertain significance ★ ⚠ same type
BCAN p.Ala357Thr Uncertain significance ★ ⚠ same type
BCAN p.Ala357Val Uncertain significance ★ ⚠ 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/bcan-p-leu840phe (accessed [today's date]).

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