Is BORCS6 p.Pro251Ala (c.751C>G) pathogenic?

BORCS6 p.Pro251Ala (c.751C>G) is classified Uncertain significance in BORCS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.0673); Very rare (popmax 8.56e-05%, nfe).

How common is BORCS6 p.Pro251Ala (c.751C>G) in the general population?

BORCS6 p.Pro251Ala (c.751C>G) is very rare (popmax 8.56e-05%, nfe) (gnomAD).

What do computational predictors say about BORCS6 p.Pro251Ala (c.751C>G)?

AlphaMissense predicts likely benign (score 0.0673) — an in-silico prediction, not a clinical call.

BORCS6 p.Pro251Ala

c.751C>G · VCV4214832

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0673 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.56e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0673	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -7.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP -0.13, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 1,070 bp · p 0.93 · regional, not allelic
Overall
CADD	19.86	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.56e-05% European (non-Finnish) · 1/1,168,628 alleles

Overall 6.29e-05% 1/1,590,918 alleles · very rare exomes 1/1,438,560 · genomes 0/152,358 · 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: BORCS6
Protein: p.Pro251Ala
Coding: c.751C>G
MANE Select: NM_017622
Type: single nucleotide variant
Location: chr17:8189390 (GRCh38)
Gene constraint: LOEUF 1.683 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.53
Residue 251: the 'disordered' region

Full BORCS6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BORCS6 p.Ala244Glu Uncertain significance ★ ⚠ same type
BORCS6 p.Ala244Gly Uncertain significance ★ ⚠ same type
BORCS6 p.Ala285Val Uncertain significance ★ ⚠ same type
BORCS6 p.Ala339Ser Uncertain significance ★ ⚠ same type
BORCS6 p.Ala91Pro Uncertain significance ★ ⚠ same type
BORCS6 p.Arg109Trp Uncertain significance ★ ⚠ same type
BORCS6 p.Arg269Trp Uncertain significance ★ ⚠ same type
BORCS6 p.Arg274Gln 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/borcs6-p-pro251ala (accessed [today's date]).

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