Is BCS1L p.Phe147= (c.441C>T) pathogenic?

BCS1L p.Phe147= (c.441C>T) is classified Likely pathogenic in BCS1L (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-18). Very rare (popmax 0.000254%, nfe); Associated with GRACILE syndrome.

What condition is associated with BCS1L p.Phe147= (c.441C>T)?

BCS1L p.Phe147= (c.441C>T) is associated with GRACILE syndrome, mitochondrial complex III deficiency nuclear type 1 (ClinVar).

How common is BCS1L p.Phe147= (c.441C>T) in the general population?

BCS1L p.Phe147= (c.441C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

How is GRACILE syndrome inherited?

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

BCS1L p.Phe147=

c.441C>T · rs2106324466 · VCV1252010

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

GRACILE syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.35	donor gain · deltas
Pangolin	Δ0.29	loss · gain 0.27 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 6	GERP 2.5, phastCons 1
Overall
CADD	18.11	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,036 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,188 alleles · very rare exomes 3/1,461,882 · genomes 0/152,306 · 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: BCS1L
Protein: p.Phe147=
Coding: c.441C>T
MANE Select: NM_001079866
dbSNP: rs2106324466
Type: single nucleotide variant
Location: chr2:218661526 (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

Also linked: mitochondrial complex III deficiency nuclear type 1

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-phe147 (accessed [today's date]).

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