Is BCS1L p.Pro99Ala (c.295C>G) pathogenic?

BCS1L p.Pro99Ala (c.295C>G) is classified Conflicting classifications of pathogenicity in BCS1L (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-11-27). AlphaMissense: likely pathogenic (0.6153); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with BCS1L p.Pro99Ala (c.295C>G)?

BCS1L p.Pro99Ala (c.295C>G) is associated with Inborn genetic diseases (ClinVar).

How common is BCS1L p.Pro99Ala (c.295C>G) in the general population?

BCS1L p.Pro99Ala (c.295C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BCS1L p.Pro99Ala (c.295C>G)?

AlphaMissense predicts likely pathogenic (score 0.6153) — an in-silico prediction, not a clinical call.

BCS1L p.Pro99Ala

c.295C>G · VCV3480321

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6153 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6153	likely pathogenic
REVEL	0.893	moderately pathogenic-leaning
SaProt	LLR -11.09	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	25.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BCS1L
Protein: p.Pro99Ala
Coding: c.295C>G
MANE Select: NM_001079866
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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BCS1L p.Pro99Leu Pathogenic ★★ same residue
BCS1L p.Pro99Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
BCS1L p.Arg177Cys Uncertain significance ★★ ⚠ same condition
BCS1L p.Arg44Trp Uncertain significance ★★ ⚠ same condition
BCS1L p.Arg69His Uncertain significance ★★ ⚠ same condition
BCS1L p.Gln195His Uncertain significance ★★ ⚠ same condition
BCS1L p.Gly303Arg Uncertain significance ★★ ⚠ same condition
BCS1L p.Ile411Ser Uncertain significance ★★ ⚠ 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-pro99ala (accessed [today's date]).

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