Is SF3B3 p.Arg697Cys (c.2089C>T) pathogenic?

SF3B3 p.Arg697Cys (c.2089C>T) is classified Uncertain significance in SF3B3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-12). AlphaMissense: likely pathogenic (0.6326); Very rare (popmax 0.000678%, nfe).

How common is SF3B3 p.Arg697Cys (c.2089C>T) in the general population?

SF3B3 p.Arg697Cys (c.2089C>T) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about SF3B3 p.Arg697Cys (c.2089C>T)?

AlphaMissense predicts likely pathogenic (score 0.6326) — an in-silico prediction, not a clinical call.

SF3B3 p.Arg697Cys

c.2089C>T · VCV3317827

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6326 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6326	likely pathogenic
REVEL	0.55	indeterminate
SaProt	LLR -13.03	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 9,390 bp · p 2e-22 · regional, not allelic
Overall
CADD	33.0	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000678% European (non-Finnish) · 8/1,179,812 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000547% 8/1,461,540 alleles · very rare

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: SF3B3
Protein: p.Arg697Cys
Coding: c.2089C>T
MANE Select: NM_012426
Type: single nucleotide variant
Location: chr16:70560547 (GRCh38)
Gene constraint: LOEUF 0.285 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 92.36 · 67 PDB
Residue 697: an α-helix

Full SF3B3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SAP130 p.Gln61Ter Likely pathogenic ★ same type
SAP130 p.Ala11Gly Uncertain significance ★ ⚠ same type
SAP130 p.Ala281Val Uncertain significance ★ ⚠ same type
SAP130 p.Ala282Val Uncertain significance ★ ⚠ same type
SAP130 p.Ala310Ser Uncertain significance ★ ⚠ same type
SAP130 p.Ala35Thr Uncertain significance ★ ⚠ same type
SAP130 p.Ala444Thr Uncertain significance ★ ⚠ same type
SAP130 p.Ala501Thr 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/sf3b3-p-arg697cys (accessed [today's date]).

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