Is BCS1L p.Pro274= (c.822G>A) pathogenic?

BCS1L p.Pro274= (c.822G>A) is classified Conflicting classifications of pathogenicity in BCS1L (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-14). Rare (popmax 0.41%, eas); Associated with mitochondrial complex III deficiency nuclear type 1.

How common is BCS1L p.Pro274= (c.822G>A) in the general population?

BCS1L p.Pro274= (c.822G>A) is rare (popmax 0.41%, eas) (gnomAD).

BCS1L p.Pro274=

Q: What condition is associated with BCS1L p.Pro274= (c.822G>A)?

BCS1L p.Pro274= (c.822G>A) is associated with mitochondrial complex III deficiency nuclear type 1, Leigh syndrome, GRACILE syndrome (ClinVar).

c.822G>A · rs112329020 · VCV334360

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.41%, eas)

Conditions

mitochondrial complex III deficiency nuclear type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.164	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -11	GERP -5
Overall
CADD	0.231	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.41% East Asian · 184/44,882 alleles

Filtering AF 0.361% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.343%

Overall 0.0162% 262/1,614,176 alleles · rare exomes 236/1,461,866 · genomes 26/152,310 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.41%	244
African / African-American	0.0306%	3,263
South Asian	0.0231%	4,337
Admixed American	0.01%	10,004
Remaining individualsnot grpmax-eligible	0.008%	12,501
European (non-Finnish)	0.00195%	51,306

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.Pro274=
Coding: c.822G>A
MANE Select: NM_001079866
dbSNP: rs112329020
Type: single nucleotide variant
Location: chr2:218662612 (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

mitochondrial complex III deficiency nuclear type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Leigh syndrome GRACILE syndrome

Similar variants

BCS1L p.Pro274Leu Uncertain significance ★★ ⚠ same residue
BCS1L p.Pro274fs Pathogenic ★★ same residue
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

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-pro274 (accessed [today's date]).

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