Is BDNF p.Thr91Lys (c.272C>A) pathogenic?

BDNF p.Thr91Lys (c.272C>A) is classified Uncertain significance in BDNF (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-07-10). AlphaMissense: ambiguous (0.3845); Very rare (popmax 0.00333%, amr); Associated with BDNF-related disorder.

What condition is associated with BDNF p.Thr91Lys (c.272C>A)?

BDNF p.Thr91Lys (c.272C>A) is associated with BDNF-related disorder (ClinVar).

How common is BDNF p.Thr91Lys (c.272C>A) in the general population?

BDNF p.Thr91Lys (c.272C>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about BDNF p.Thr91Lys (c.272C>A)?

AlphaMissense predicts ambiguous (score 0.3845) — an in-silico prediction, not a clinical call.

BDNF p.Thr91Lys

c.272C>A · VCV3354074

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3845 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

BDNF-related disorder

Computational evidence

Protein change
AlphaMissense	0.3845	ambiguous
REVEL	0.283	benign-leaning
SaProt	LLR -6.77	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.9, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 375 bp · p 0.013 · regional, not allelic
Overall
CADD	23.1	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 0.00333% Admixed American · 2/60,012 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.00031% 5/1,613,992 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,006
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.000169%	590,019

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.Thr91Lys
Coding: c.272C>A
MANE Select: NM_001709
Type: single nucleotide variant
Location: chr11:27658293 (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

BDNF-related disorder

Similar variants

BDNF p.Thr91= Likely benign ★ same residue
BDNF c.-21-15487T>G Uncertain significance ★ same condition
BDNF c.-21-15496C>G Uncertain significance ★ same condition
BDNF p.Arg38Gln Uncertain significance ★ ⚠ same condition
BDNF p.Gly31Asp Uncertain significance ★ ⚠ same condition
BDNF p.Lys76Glu Uncertain significance ★ ⚠ same condition
BDNF p.Met220Thr Uncertain significance ★ same condition
BDNF c.-21-15481C>A 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-thr91lys (accessed [today's date]).

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