Is SBF1 p.Pro199Ser (c.595C>T) pathogenic?

SBF1 p.Pro199Ser (c.595C>T) is classified Benign in SBF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-12). AlphaMissense: ambiguous (0.5431); Very rare (popmax 0.000175%, nfe); Associated with Tip-toe gait.

What condition is associated with SBF1 p.Pro199Ser (c.595C>T)?

SBF1 p.Pro199Ser (c.595C>T) is associated with Tip-toe gait (ClinVar).

How common is SBF1 p.Pro199Ser (c.595C>T) in the general population?

SBF1 p.Pro199Ser (c.595C>T) is very rare (popmax 0.000175%, nfe) (gnomAD).

What do computational predictors say about SBF1 p.Pro199Ser (c.595C>T)?

AlphaMissense predicts ambiguous (score 0.5431) — an in-silico prediction, not a clinical call.

SBF1 p.Pro199Ser

c.595C>T · VCV4852327

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5431 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000175%, nfe)

Conditions

Tip-toe gait

Computational evidence

Protein change
AlphaMissense	0.5431	ambiguous
REVEL	0.358	indeterminate
SaProt	LLR -8.06	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 8,372 bp · p 0.4 · regional, not allelic
Overall
CADD	24.8	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 P200S vs ClinVar P199S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000175% European (non-Finnish) · 2/1,146,132 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000129% 2/1,549,574 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: SBF1
Protein: p.Pro199Ser
Coding: c.595C>T
MANE Select: NM_002972
Type: single nucleotide variant
Location: chr22:50466665 (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.Pro199= 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
SBF1 p.Val318Met 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-pro199ser (accessed [today's date]).

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