Is BDNF p.Asp74Ala (c.221A>C) pathogenic?

BDNF p.Asp74Ala (c.221A>C) is classified Uncertain significance in BDNF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-08). AlphaMissense: likely benign (0.1222); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with BDNF p.Asp74Ala (c.221A>C)?

BDNF p.Asp74Ala (c.221A>C) is associated with Inborn genetic diseases (ClinVar).

How common is BDNF p.Asp74Ala (c.221A>C) in the general population?

BDNF p.Asp74Ala (c.221A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BDNF p.Asp74Ala (c.221A>C)?

AlphaMissense predicts likely benign (score 0.1222) — an in-silico prediction, not a clinical call.

BDNF p.Asp74Ala

c.221A>C · VCV3824102

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1222 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1222	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -6.96	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 5.1	GERP 1.8, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 375 bp · p 0.013 · regional, not allelic
Overall
CADD	19.84	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BDNF
Protein: p.Asp74Ala
Coding: c.221A>C
MANE Select: NM_001709
Type: single nucleotide variant
Location: chr11:27658344 (GRCh38)
Gene constraint: LOEUF 0.233 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.44 · 2 PDB

Full BDNF 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

BDNF p.Asp86= Likely benign ★★ same condition
BDNF p.Thr149= Likely benign ★★ same condition
BDNF p.Glu168Ter Likely pathogenic ★ same condition
BDNF p.Ala24Thr Uncertain significance ★ ⚠ same condition
BDNF p.Ala51Val Uncertain significance ★ ⚠ same condition
BDNF p.Arg78Gln Uncertain significance ★ ⚠ same condition
BDNF p.Glu111Gln Uncertain significance ★ ⚠ same condition
BDNF p.Gly55Ser 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/bdnf-p-asp74ala (accessed [today's date]).

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