Is BICRAL p.Pro676Ser (c.2026C>T) pathogenic?

BICRAL p.Pro676Ser (c.2026C>T) is classified Uncertain significance in BICRAL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-28). AlphaMissense: likely benign (0.0683); Ultra-rare (popmax 0.0423%, eas).

How common is BICRAL p.Pro676Ser (c.2026C>T) in the general population?

BICRAL p.Pro676Ser (c.2026C>T) is ultra-rare (popmax 0.0423%, eas) (gnomAD).

What do computational predictors say about BICRAL p.Pro676Ser (c.2026C>T)?

AlphaMissense predicts likely benign (score 0.0683) — an in-silico prediction, not a clinical call.

BICRAL p.Pro676Ser

c.2026C>T · VCV3480651

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0683 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0423%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0683	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -4.81	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 5.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 28 kb · p 7.8e-13 · regional, not allelic
Overall
CADD	19.42	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 0.0423% East Asian · 19/44,878 alleles

Filtering AF 0.0277% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.023%

Overall 0.00124% 20/1,611,602 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0423%	2,362
Remaining individualsnot grpmax-eligible	0.0016%	62,442

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: BICRAL
Protein: p.Pro676Ser
Coding: c.2026C>T
MANE Select: NM_001393499
Type: single nucleotide variant
Location: chr6:42853718 (GRCh38)
Gene constraint: LOEUF 0.127 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 46.40
Residue 676: the 'disordered' region

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

Similar variants

BICRAL p.Ala42Val Uncertain significance ★ ⚠ same type
BICRAL p.Ala479Gly Uncertain significance ★ ⚠ same type
BICRAL p.Ala546Gly Uncertain significance ★ ⚠ same type
BICRAL p.Ala695Val Uncertain significance ★ ⚠ same type
BICRAL p.Ala729Val Uncertain significance ★ ⚠ same type
BICRAL p.Ala833Asp Uncertain significance ★ ⚠ same type
BICRAL p.Ala889Thr Uncertain significance ★ ⚠ same type
BICRAL p.Arg1022Gln 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/bicral-p-pro676ser (accessed [today's date]).

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