Is BMAL1 p.Pro535Ser (c.1603C>T) pathogenic?

BMAL1 p.Pro535Ser (c.1603C>T) is classified Uncertain significance in BMAL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely benign (0.099); Ultra-rare (popmax 0.0178%, nfe).

How common is BMAL1 p.Pro535Ser (c.1603C>T) in the general population?

BMAL1 p.Pro535Ser (c.1603C>T) is ultra-rare (popmax 0.0178%, nfe) (gnomAD).

What do computational predictors say about BMAL1 p.Pro535Ser (c.1603C>T)?

AlphaMissense predicts likely benign (score 0.099) — an in-silico prediction, not a clinical call.

BMAL1 p.Pro535Ser

c.1603C>T · rs140277154 · VCV2476586

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.099 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.099	likely benign
REVEL	0.239	benign-leaning
SaProt	LLR -5.22	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 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 11 kb · p 0.00035 · regional, not allelic
Overall
CADD	23.3	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 0.0178% European (non-Finnish) · 210/1,179,890 alleles

Filtering AF 0.0158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.0137% 221/1,613,836 alleles · ultra-rare exomes 214/1,461,626 · genomes 7/152,210 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0178%	5,619
Remaining individualsnot grpmax-eligible	0.016%	6,248
African / African-American	0.00133%	74,926

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: BMAL1
Protein: p.Pro535Ser
Coding: c.1603C>T
MANE Select: NM_001297719
dbSNP: rs140277154
Type: single nucleotide variant
Location: chr11:13381240 (GRCh38)
Structure: AlphaFold pLDDT 67.00 · 3 PDB
Residue 535: the 'interaction with ciart' region; the 'disordered' region

Full BMAL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BMAL1 c.140+7C>T Uncertain significance ★ same type
BMAL1 p.Ala359Pro Uncertain significance ★ ⚠ same type
BMAL1 p.Arg166Ter Uncertain significance ★ same type
BMAL1 p.Arg238Gly Uncertain significance ★ ⚠ same type
BMAL1 p.Arg276Ter Uncertain significance ★ same type
BMAL1 p.Arg343Trp Uncertain significance ★ ⚠ same type
BMAL1 p.Arg37Cys Uncertain significance ★ ⚠ same type
BMAL1 p.Arg497Gln 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/bmal1-p-pro535ser (accessed [today's date]).

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