Is BDNF p.Thr2Ile (c.5C>T) pathogenic?

BDNF p.Thr2Ile (c.5C>T) is classified Conflicting classifications of pathogenicity in BDNF (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-15). AlphaMissense: likely pathogenic (0.8237); Rare (popmax 0.379%, mid); Associated with obesity disorder.

What condition is associated with BDNF p.Thr2Ile (c.5C>T)?

BDNF p.Thr2Ile (c.5C>T) is associated with obesity disorder, central hypoventilation syndrome, congenital (ClinVar).

How common is BDNF p.Thr2Ile (c.5C>T) in the general population?

BDNF p.Thr2Ile (c.5C>T) is rare (popmax 0.379%, mid) (gnomAD).

What do computational predictors say about BDNF p.Thr2Ile (c.5C>T)?

AlphaMissense predicts likely pathogenic (score 0.8237) — an in-silico prediction, not a clinical call.

BDNF p.Thr2Ile

c.5C>T · rs8192466 · VCV17696

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8237 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.379%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

obesity disorder

Computational evidence

Protein change
AlphaMissense	0.8237	likely pathogenic
REVEL	0.405	indeterminate
SaProt	LLR -4.18	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 375 bp · p 0.013 · regional, not allelic
Overall
CADD	23.6	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 0.379% Middle Eastern · 23/6,062 alleles

Filtering AF 0.26% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.257%

Overall 0.221% 3,565/1,614,178 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.379%	264
Remaining individualsnot grpmax-eligible	0.269%	372
European (non-Finnish)	0.268%	373
South Asian	0.0955%	1,047
Finnishnot grpmax-eligible	0.0921%	1,085
Admixed American	0.0716%	1,396
African / African-American	0.0266%	3,753

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.Thr2Ile
Coding: c.5C>T
MANE Select: NM_001709
dbSNP: rs8192466
Type: single nucleotide variant
Location: chr11:27658560 (GRCh38)
Gene constraint: LOEUF 0.233 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.44 · 2 PDB
Residue 2: a UniProt-annotated variant site (found in a patient with congenital central hypoventilation syndrome; uncertain significance)

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

Disease context

obesity disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: central hypoventilation syndrome, congenital

Similar variants

BDNF p.Thr2Asn Uncertain significance ★ ⚠ same residue
BDNF p.Cys186Tyr Likely pathogenic ★ same condition
BDNF c.-21-15633G>A Benign same condition
BDNF c.-21-1044G>C Benign ★★ same type
BDNF c.-21-1065G>A Benign ★★ same type
BDNF c.-21-15778G>T Benign ★★ same type
BDNF c.-22+774G>A Benign ★★ same type
BDNF p.Ala150= Benign ★★ 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/bdnf-p-thr2ile (accessed [today's date]).

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