Is BDNF p.Val46Met (c.136G>A) pathogenic?

BDNF p.Val46Met (c.136G>A) is classified Uncertain significance in BDNF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-27). AlphaMissense: likely benign (0.0687); Ultra-rare (popmax 0.028%, afr); Associated with BDNF-related disorder.

What condition is associated with BDNF p.Val46Met (c.136G>A)?

BDNF p.Val46Met (c.136G>A) is associated with BDNF-related disorder (ClinVar).

How common is BDNF p.Val46Met (c.136G>A) in the general population?

BDNF p.Val46Met (c.136G>A) is ultra-rare (popmax 0.028%, afr) (gnomAD).

What do computational predictors say about BDNF p.Val46Met (c.136G>A)?

AlphaMissense predicts likely benign (score 0.0687) — an in-silico prediction, not a clinical call.

BDNF p.Val46Met

c.136G>A · rs146354977 · VCV2636085

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0687 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.028%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BDNF-related disorder

Computational evidence

Protein change
AlphaMissense	0.0687	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -7.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -4.1	GERP -5.8
Regional constraint	o/e 0.80	unconstrained · MANE · 375 bp · p 0.013 · regional, not allelic
Overall
CADD	13.54	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 0.028% African / African-American · 21/75,050 alleles

Filtering AF 0.0187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.00198% 32/1,614,218 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.028%	3,574
Admixed American	0.00333%	30,016
East Asian	0.00223%	44,880
European (non-Finnish)	0.000678%	147,506

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: BDNF
Protein: p.Val46Met
Coding: c.136G>A
dbSNP: rs146354977
Type: single nucleotide variant
Location: chr11:27658429 (GRCh38)

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

Disease context

BDNF-related disorder

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/bdnf-p-val46met (accessed [today's date]).

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