Is SBF1 p.Arg656Trp (c.1966C>T) pathogenic?

SBF1 p.Arg656Trp (c.1966C>T) is classified Conflicting classifications of pathogenicity in SBF1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-28). AlphaMissense: likely pathogenic (0.9725); Very rare (popmax 0.004%, afr); Associated with Tip-toe gait.

What condition is associated with SBF1 p.Arg656Trp (c.1966C>T)?

SBF1 p.Arg656Trp (c.1966C>T) is associated with Tip-toe gait (ClinVar).

How common is SBF1 p.Arg656Trp (c.1966C>T) in the general population?

SBF1 p.Arg656Trp (c.1966C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about SBF1 p.Arg656Trp (c.1966C>T)?

AlphaMissense predicts likely pathogenic (score 0.9725) — an in-silico prediction, not a clinical call.

SBF1 p.Arg656Trp

c.1966C>T · rs568904413 · VCV2171993

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9725 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Tip-toe gait

Computational evidence

Protein change
AlphaMissense	0.9725	likely pathogenic
REVEL	0.528	indeterminate
SaProt	LLR -11.05	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 4.8	GERP 0.13, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 19 kb · p 0.67 · regional, not allelic
Overall
CADD	24.0	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 R657W vs ClinVar R656W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/75,024 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000494%

Overall 0.000558% 9/1,613,110 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	25,008
Finnishnot grpmax-eligible	0.00158%	63,234
South Asian	0.0011%	91,046
European (non-Finnish)	0.000339%	294,977

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: SBF1
Protein: p.Arg656Trp
Coding: c.1966C>T
MANE Select: NM_002972
dbSNP: rs568904413
Type: single nucleotide variant
Location: chr22:50462872 (GRCh38)
Gene constraint: LOEUF 0.381 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.72

Full SBF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Tip-toe gait — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SBF1 p.Arg656Gln Uncertain significance ★ ⚠ same residue
SBF1 p.Arg656= Likely benign ★ same residue
SBF1 c.2967+8G>A Benign/Likely benign ★★ same condition
SBF1 p.Leu307Val Benign/Likely benign ★★ same condition
SBF1 p.Ala723Val Likely pathogenic ★ ⚠ same condition
SBF1 p.Leu1355Val Likely pathogenic ★ ⚠ same condition
SBF1 p.Met800Arg Likely pathogenic ★ ⚠ same condition
SBF1 p.Pro1631Leu Likely pathogenic ★ ⚠ 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/sbf1-p-arg656trp (accessed [today's date]).

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