Is BICRA p.Pro683Ser (c.2047C>T) pathogenic?

BICRA p.Pro683Ser (c.2047C>T) is classified Benign in BICRA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2020-01-21). AlphaMissense: likely benign (0.0528); Common (popmax 43.4%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about BICRA p.Pro683Ser (c.2047C>T)?

AlphaMissense predicts likely benign (score 0.0528) — an in-silico prediction, not a clinical call.

BICRA p.Pro683Ser

Q: How common is BICRA p.Pro683Ser (c.2047C>T) in the general population?

BICRA p.Pro683Ser (c.2047C>T) is common (popmax 43.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2047C>T · rs3745762 · VCV1257456

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0528 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 43.4%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0528	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -6.22	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 0.83	GERP 1.7, phastCons 0.22
Regional constraint	o/e 1.15	unconstrained · MANE · 19 kb · p 1.1e-07 · regional, not allelic
Overall
CADD	10.29	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 43.4% African / African-American · 31,706/73,050 alleles

Filtering AF 43% ClinGen BA1/BS1 input FAF95, joint · FAF99 42.8%

Overall 27.9% 428,623/1,534,728 alleles · common exomes 380,579/1,382,706 · genomes 48,044/152,022 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	43.4%	2
South Asian	32.7%	3
Ashkenazi Jewishnot grpmax-eligible	31.2%	3
Middle Eastern	30%	3
Amishnot grpmax-eligible	29.5%	3
Admixed American	29.4%	3
East Asian	29.1%	3
Remaining individualsnot grpmax-eligible	28.9%	3
European (non-Finnish)	26.5%	4
Finnishnot grpmax-eligible	24.3%	4

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: BICRA
Protein: p.Pro683Ser
Coding: c.2047C>T
MANE Select: NM_001394372
dbSNP: rs3745762
Type: single nucleotide variant
Location: chr19:47681217 (GRCh38)
Gene constraint: LOEUF 0.659 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 42.79
Residue 683: the 'disordered' region; a UniProt-annotated variant site (in css12); a UniProt-annotated variant site (in)

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

Similar variants

BICRA p.Gln290Ter Pathogenic/Likely pathogenic ★★ same type
BICRA p.Ala1110Thr Uncertain significance ★★ ⚠ same type
BICRA p.Ala313Pro Uncertain significance ★★ ⚠ same type
BICRA p.Ala579Thr Uncertain significance ★★ ⚠ same type
BICRA p.Arg1384Cys Uncertain significance ★★ ⚠ same type
BICRA p.Arg802Cys Uncertain significance ★★ ⚠ same type
BICRA p.Asn408Lys Uncertain significance ★★ ⚠ same type
BICRA p.Gly441Arg 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/bicra-p-pro683ser (accessed [today's date]).

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