Is BOC p.Arg708Cys (c.2122C>T) pathogenic?

BOC p.Arg708Cys (c.2122C>T) is classified Uncertain significance in BOC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely pathogenic (0.584); Ultra-rare (popmax 0.0164%, mid).

How common is BOC p.Arg708Cys (c.2122C>T) in the general population?

BOC p.Arg708Cys (c.2122C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about BOC p.Arg708Cys (c.2122C>T)?

AlphaMissense predicts likely pathogenic (score 0.584) — an in-silico prediction, not a clinical call.

BOC p.Arg708Cys

c.2122C>T · VCV4214688

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.584 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.584	likely pathogenic
REVEL	0.332	indeterminate
SaProt	LLR -10.70	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 37 kb · p 1.8e-07 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

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

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R707C vs ClinVar R708C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000929% 15/1,613,842 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Admixed American	0.00333%	29,991
East Asian	0.00223%	44,880
Remaining individualsnot grpmax-eligible	0.0016%	62,480
South Asian	0.0011%	91,060
European (non-Finnish)	0.000763%	131,108

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: BOC
Protein: p.Arg708Cys
Coding: c.2122C>T
MANE Select: NM_001378074
Type: single nucleotide variant
Location: chr3:113279922 (GRCh38)
Gene constraint: LOEUF 0.789 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.98 · 3 PDB

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

Similar variants

BOC p.Ala715= Benign ★★ same type
BOC p.Lys884Asn Benign ★★ ⚠ same type
BOC p.Pro829Arg Benign ★★ ⚠ same type
BOC p.Pro913Ser Benign ★★ same type
BOC p.Ala226Thr Uncertain significance ★ ⚠ same type
BOC p.Ala424Thr Uncertain significance ★ ⚠ same type
BOC p.Ala470Val Uncertain significance ★ ⚠ same type
BOC p.Ala503Val 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/boc-p-arg708cys (accessed [today's date]).

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