Is BMAL2 p.Arg118Trp (c.352C>T) pathogenic?

BMAL2 p.Arg118Trp (c.352C>T) is classified Uncertain significance in BMAL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: ambiguous (0.505); Very rare (popmax 0.00878%, sas).

How common is BMAL2 p.Arg118Trp (c.352C>T) in the general population?

BMAL2 p.Arg118Trp (c.352C>T) is very rare (popmax 0.00878%, sas) (gnomAD).

What do computational predictors say about BMAL2 p.Arg118Trp (c.352C>T)?

AlphaMissense predicts ambiguous (score 0.505) — an in-silico prediction, not a clinical call.

BMAL2 p.Arg118Trp

c.352C>T · rs140062821 · VCV2521509

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.505 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00878%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.505	ambiguous
REVEL	0.772	pathogenic-leaning
SaProt	LLR -12.80	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.7	GERP -3.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 87 kb · p 0.025 · regional, not allelic
Overall
CADD	25.5	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 0.00878% South Asian · 8/91,066 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00304% 49/1,614,022 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00878%	11,383
European (non-Finnish)	0.00331%	30,255
Remaining individualsnot grpmax-eligible	0.0032%	31,254

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.Arg118Trp
Coding: c.352C>T
MANE Select: NM_020183
dbSNP: rs140062821
Type: single nucleotide variant
Location: chr12:27380272 (GRCh38)
Structure: AlphaFold pLDDT 61.96 · 1 PDB
Residue 118: 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.Arg118Gln 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.Arg142His Uncertain significance ★ ⚠ same type
BMAL2 p.Arg173Ile Uncertain significance ★ ⚠ same type
BMAL2 p.Arg273Cys 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-arg118trp (accessed [today's date]).

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