Is BCS1L p.Pro101= (c.303T>G) pathogenic?

BCS1L p.Pro101= (c.303T>G) is classified Likely benign in BCS1L (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-30). Ultra-rare (popmax 0.0139%, nfe); Associated with GRACILE syndrome.

What condition is associated with BCS1L p.Pro101= (c.303T>G)?

BCS1L p.Pro101= (c.303T>G) is associated with GRACILE syndrome (ClinVar).

How common is BCS1L p.Pro101= (c.303T>G) in the general population?

BCS1L p.Pro101= (c.303T>G) is ultra-rare (popmax 0.0139%, nfe) (gnomAD).

How is GRACILE syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

BCS1L p.Pro101=

c.303T>G · rs138756092 · VCV742568

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0139%, nfe)

Conditions

GRACILE syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.037	GERP -1.1, phastCons 0.97
Overall
CADD	8.957	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0139% European (non-Finnish) · 164/1,180,040 alleles

Filtering AF 0.0121% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0115%

Overall 0.0112% 181/1,614,198 alleles · ultra-rare exomes 165/1,461,890 · genomes 16/152,308 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0139%	7,195
African / African-American	0.0107%	9,381
Remaining individualsnot grpmax-eligible	0.0064%	15,625
Finnishnot grpmax-eligible	0.00469%	21,344
Admixed American	0.00333%	30,011

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: BCS1L
Protein: p.Pro101=
Coding: c.303T>G
MANE Select: NM_001079866
dbSNP: rs138756092
Type: single nucleotide variant
Location: chr2:218661290 (GRCh38)
Gene constraint: LOEUF 0.958 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.10

Full BCS1L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

GRACILE syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For GRACILE syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

BCS1L c.320+1G>T Pathogenic/Likely pathogenic ★★ same condition
BCS1L c.889+1G>T Pathogenic/Likely pathogenic ★★ same condition
BCS1L c.889+2T>G Likely pathogenic ★★ same condition
BCS1L c.-50+388C>G Likely pathogenic ★★ same condition
BCS1L c.-50+405A>G Pathogenic/Likely pathogenic ★★ same condition
BCS1L p.Arg109Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
BCS1L p.Arg114Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
BCS1L p.Arg117Ter Pathogenic/Likely pathogenic ★★ same condition

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/bcs1l-p-pro101 (accessed [today's date]).

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