Is BMAL2 p.Leu147Phe (c.439C>T) pathogenic?

BMAL2 p.Leu147Phe (c.439C>T) is classified Uncertain significance in BMAL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: likely pathogenic (0.9476); Very rare (popmax 0.00446%, eas).

How common is BMAL2 p.Leu147Phe (c.439C>T) in the general population?

BMAL2 p.Leu147Phe (c.439C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about BMAL2 p.Leu147Phe (c.439C>T)?

AlphaMissense predicts likely pathogenic (score 0.9476) — an in-silico prediction, not a clinical call.

BMAL2 p.Leu147Phe

c.439C>T · rs757966482 · VCV3134480

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9476 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9476	likely pathogenic · top 4% in BMAL2
REVEL	0.823	moderately pathogenic-leaning
SaProt	LLR -11.75	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 87 kb · p 0.025 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00446% East Asian · 2/44,878 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000137% 2/1,461,856 alleles · very rare

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: BMAL2
Protein: p.Leu147Phe
Coding: c.439C>T
MANE Select: NM_020183
dbSNP: rs757966482
Type: single nucleotide variant
Location: chr12:27380359 (GRCh38)
Structure: AlphaFold pLDDT 61.96 · 1 PDB
Residue 147: the bhlh domain; the 'interaction with per2' region

Full BMAL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BMAL2 p.Leu147Ile Uncertain significance ★ ⚠ same residue
BMAL2 p.Ala141Val Uncertain significance ★ ⚠ same type
BMAL2 p.Ala388Thr Uncertain significance ★ ⚠ same type
BMAL2 p.Ala3Thr Uncertain significance ★ ⚠ same type
BMAL2 p.Ala583Thr Uncertain significance ★ ⚠ same type
BMAL2 p.Arg118Gln Uncertain significance ★ ⚠ same type
BMAL2 p.Arg118Trp Uncertain significance ★ ⚠ same type
BMAL2 p.Arg142His 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/bmal2-p-leu147phe (accessed [today's date]).

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