Is BMAL1 p.Pro625Gln (c.1874C>A) pathogenic?

BMAL1 p.Pro625Gln (c.1874C>A) is classified Uncertain significance in BMAL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-28). AlphaMissense: likely pathogenic (0.9712); Very rare (popmax 0.000932%, nfe).

How common is BMAL1 p.Pro625Gln (c.1874C>A) in the general population?

BMAL1 p.Pro625Gln (c.1874C>A) is very rare (popmax 0.000932%, nfe) (gnomAD).

What do computational predictors say about BMAL1 p.Pro625Gln (c.1874C>A)?

AlphaMissense predicts likely pathogenic (score 0.9712) — an in-silico prediction, not a clinical call.

BMAL1 p.Pro625Gln

c.1874C>A · rs768084035 · VCV3134456

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9712 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9712	likely pathogenic
REVEL	0.4	indeterminate
SaProt	LLR -7.68	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 11 kb · p 0.00035 · regional, not allelic
Overall
CADD	24.1	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 0.000932% European (non-Finnish) · 11/1,179,834 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000682% 11/1,613,750 alleles · very rare exomes 7/1,461,596 · genomes 4/152,154 · joint denominator

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.Pro625Gln
Coding: c.1874C>A
MANE Select: NM_001297719
dbSNP: rs768084035
Type: single nucleotide variant
Location: chr11:13386749 (GRCh38)
Structure: AlphaFold pLDDT 67.00 · 3 PDB

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-pro625gln (accessed [today's date]).

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