Is BMAL2 p.Ser467Cys (c.1400C>G) pathogenic?

BMAL2 p.Ser467Cys (c.1400C>G) is classified Uncertain significance in BMAL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-10). AlphaMissense: likely benign (0.18); Very rare (popmax 0.000171%, nfe).

How common is BMAL2 p.Ser467Cys (c.1400C>G) in the general population?

BMAL2 p.Ser467Cys (c.1400C>G) is very rare (popmax 0.000171%, nfe) (gnomAD).

What do computational predictors say about BMAL2 p.Ser467Cys (c.1400C>G)?

AlphaMissense predicts likely benign (score 0.18) — an in-silico prediction, not a clinical call.

BMAL2 p.Ser467Cys

c.1400C>G · VCV4214219

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.18 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000171%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.18	likely benign
REVEL	0.286	benign-leaning
SaProt	LLR -8.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.21	donor gain · deltas
Pangolin	Δ0.21	gain · loss 0.15 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 87 kb · p 0.025 · regional, not allelic
Overall
CADD	23.1	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 0.000171% European (non-Finnish) · 2/1,170,066 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000139% 2/1,440,020 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.Ser467Cys
Coding: c.1400C>G
MANE Select: NM_020183
Type: single nucleotide variant
Location: chr12:27401656 (GRCh38)
Structure: AlphaFold pLDDT 61.96 · 1 PDB
Residue 467: the pac domain; a β-strand

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

Similar variants

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
BMAL2 p.Arg173Ile 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-ser467cys (accessed [today's date]).

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