Is BMAL2 p.Phe629Ile (c.1885T>A) pathogenic?

BMAL2 p.Phe629Ile (c.1885T>A) is classified Uncertain significance in BMAL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-11). AlphaMissense: likely benign (0.094); Very rare (popmax 8.49e-05%, nfe).

How common is BMAL2 p.Phe629Ile (c.1885T>A) in the general population?

BMAL2 p.Phe629Ile (c.1885T>A) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about BMAL2 p.Phe629Ile (c.1885T>A)?

AlphaMissense predicts likely benign (score 0.094) — an in-silico prediction, not a clinical call.

BMAL2 p.Phe629Ile

c.1885T>A · rs780636694 · VCV2536000

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.094 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.094	likely benign
REVEL	0.263	benign-leaning
SaProt	LLR -7.00	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 0.94	GERP -1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 87 kb · p 0.025 · regional, not allelic
Overall
CADD	20.6	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 8.49e-05% European (non-Finnish) · 1/1,177,438 alleles

Overall 6.88e-05% 1/1,453,616 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.Phe629Ile
Coding: c.1885T>A
MANE Select: NM_020183
dbSNP: rs780636694
Type: single nucleotide variant
Location: chr12:27420506 (GRCh38)
Structure: AlphaFold pLDDT 61.96 · 1 PDB

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

Similar variants

BMAL2 p.Phe629Leu 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-phe629ile (accessed [today's date]).

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