Is BCS1L p.Pro339= (c.1017T>C) pathogenic?

BCS1L p.Pro339= (c.1017T>C) is classified Benign in BCS1L (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 44%, afr) — too common for a highly-penetrant pathogenic allele; Associated with GRACILE syndrome.

What condition is associated with BCS1L p.Pro339= (c.1017T>C)?

BCS1L p.Pro339= (c.1017T>C) is associated with GRACILE syndrome, mitochondrial complex III deficiency nuclear type 1, Leigh syndrome (ClinVar).

How is GRACILE syndrome inherited?

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

BCS1L p.Pro339=

Q: How common is BCS1L p.Pro339= (c.1017T>C) in the general population?

BCS1L p.Pro339= (c.1017T>C) is common (popmax 44%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1017T>C · rs35843327 · VCV136505

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 44%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

GRACILE syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.017	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.15	GERP -4.9, phastCons 0.99
Overall
CADD	7.883	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 44% African / African-American · 32,972/74,968 alleles

Filtering AF 43.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 43.4%

Overall 6.01% 96,954/1,614,096 alleles · common exomes 73,763/1,461,886 · genomes 23,191/152,210 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	44%	2
East Asian	11.3%	9
Middle Eastern	7.64%	13
Remaining individualsnot grpmax-eligible	7.32%	14
Admixed American	5.25%	19
South Asian	5.02%	20
Ashkenazi Jewishnot grpmax-eligible	4.94%	20
European (non-Finnish)	3.61%	28
Finnishnot grpmax-eligible	3.11%	32
Amishnot grpmax-eligible	2.3%	43

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.Pro339=
Coding: c.1017T>C
MANE Select: NM_001079866
dbSNP: rs35843327
Type: single nucleotide variant
Location: chr2:218663143 (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 Leigh syndrome Bjornstad syndrome

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.321-2A>G 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

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-pro339 (accessed [today's date]).

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