Is BCORL1 p.Arg1691Cys (c.5071C>T) pathogenic?

BCORL1 p.Arg1691Cys (c.5071C>T) is classified Likely benign in BCORL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-01). AlphaMissense: ambiguous (0.3842); Ultra-rare (popmax 0.048%, mid).

How common is BCORL1 p.Arg1691Cys (c.5071C>T) in the general population?

BCORL1 p.Arg1691Cys (c.5071C>T) is ultra-rare (popmax 0.048%, mid) (gnomAD).

What do computational predictors say about BCORL1 p.Arg1691Cys (c.5071C>T)?

AlphaMissense predicts ambiguous (score 0.3842) — an in-silico prediction, not a clinical call.

BCORL1 p.Arg1691Cys

c.5071C>T · VCV3898405

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3842 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.048%, mid)

Computational evidence

Protein change
AlphaMissense	0.3842	ambiguous
REVEL	0.256	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.9, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 17 kb · p 0.023 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R1617C vs ClinVar R1691C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.048% Middle Eastern · 2/4,165 alleles

Filtering AF 0.00846% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00353%

Overall 0.00328% 39/1,189,124 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.048%	2,083
South Asian	0.00946%	10,573
European (non-Finnish)	0.0035%	28,532
Remaining individualsnot grpmax-eligible	0.00214%	46,679

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: BCORL1
Protein: p.Arg1691Cys
Coding: c.5071C>T
MANE Select: NM_001379451
Type: single nucleotide variant
Location: chrX:130052012 (GRCh38)
Structure: AlphaFold pLDDT 38.79 · 2 PDB
Residue 1691: the 'pcgf ub-like fold domain (pufd); required for the interaction with the kdm2b-skp1 heterodimeric complex' region; a UniProt-annotated variant site (found in a sterile man with oligoasthenoteratozoospermia; likely pathogenic; loss of nuclear localization; loss of interaction with skp1)

Full BCORL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BCORL1 p.Ala261Val Uncertain significance ★★ ⚠ same type
BCORL1 p.Arg1334Gln Uncertain significance ★★ ⚠ same type
BCORL1 p.Arg1716Gln Uncertain significance ★★ ⚠ same type
BCORL1 p.Asp77Val Uncertain significance ★★ ⚠ same type
BCORL1 p.Gln1076Arg Uncertain significance ★★ ⚠ same type
BCORL1 p.Glu1201Gln Uncertain significance ★★ ⚠ same type
BCORL1 p.Glu1256Asp Uncertain significance ★★ ⚠ same type
BCORL1 p.Glu1744Lys Uncertain significance ★★ ⚠ 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/bcorl1-p-arg1691cys (accessed [today's date]).

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