Is BMAL2 p.Asp179His (c.535G>C) pathogenic?

BMAL2 p.Asp179His (c.535G>C) is classified Uncertain significance in BMAL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-25). AlphaMissense: ambiguous (0.3674); Very rare (popmax 0.00134%, afr).

How common is BMAL2 p.Asp179His (c.535G>C) in the general population?

BMAL2 p.Asp179His (c.535G>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about BMAL2 p.Asp179His (c.535G>C)?

AlphaMissense predicts ambiguous (score 0.3674) — an in-silico prediction, not a clinical call.

BMAL2 p.Asp179His

c.535G>C · VCV3481099

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3674 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3674	ambiguous
REVEL	0.287	benign-leaning
SaProt	LLR -10.69	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.4	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 87 kb · p 0.025 · regional, not allelic
Overall
CADD	22.2	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 0.00134% African / African-American · 1/74,802 alleles

Overall 6.88e-05% 1/1,453,374 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.Asp179His
Coding: c.535G>C
MANE Select: NM_020183
Type: single nucleotide variant
Location: chr12:27385531 (GRCh38)
Structure: AlphaFold pLDDT 61.96 · 1 PDB
Residue 179: the pas 1 domain; the 'interaction with per2' region

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-asp179his (accessed [today's date]).

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