Is BCS1L p.Pro99Ser (c.295C>T) pathogenic?

BCS1L p.Pro99Ser (c.295C>T) is classified Conflicting classifications of pathogenicity in BCS1L (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-07-23). AlphaMissense: likely pathogenic (0.9079); Very rare (popmax 8.47e-05%, nfe).

How common is BCS1L p.Pro99Ser (c.295C>T) in the general population?

BCS1L p.Pro99Ser (c.295C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about BCS1L p.Pro99Ser (c.295C>T)?

AlphaMissense predicts likely pathogenic (score 0.9079) — an in-silico prediction, not a clinical call.

BCS1L p.Pro99Ser

c.295C>T · rs2469868875 · VCV1952511

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9079 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9079	likely pathogenic
REVEL	0.919	moderately pathogenic-leaning
SaProt	LLR -12.05	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 2,395 bp · p 3.2e-10 · regional, not allelic
Overall
CADD	26.7	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 8.47e-05% European (non-Finnish) · 1/1,180,046 alleles

Overall 6.2e-05% 1/1,614,192 alleles · very rare exomes 1/1,461,890 · genomes 0/152,302 · 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.Pro99Ser
Coding: c.295C>T
MANE Select: NM_001079866
dbSNP: rs2469868875
Type: single nucleotide variant
Location: chr2:218661282 (GRCh38)
Gene constraint: LOEUF 0.958 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.10
Residue 99: a UniProt-annotated variant site (in mc3dn1)

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

Similar variants

BCS1L p.Pro99Leu Pathogenic ★★ same residue
BCS1L p.Pro99Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
BCS1L c.320+1G>T Pathogenic/Likely pathogenic ★★ same type
BCS1L c.321-2A>G Likely pathogenic ★★ same type
BCS1L c.889+1G>T Pathogenic/Likely pathogenic ★★ same type
BCS1L c.889+2T>G Likely pathogenic ★★ same type
BCS1L c.-50+388C>G Likely pathogenic ★★ same type
BCS1L c.-50+405A>G Pathogenic/Likely pathogenic ★★ 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/bcs1l-p-pro99ser (accessed [today's date]).

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