Is SBF1 p.Pro438Ser (c.1312C>T) pathogenic?

SBF1 p.Pro438Ser (c.1312C>T) is classified Conflicting classifications of pathogenicity in SBF1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-10-02). AlphaMissense: likely benign (0.0588); Ultra-rare (popmax 0.0246%, nfe); Associated with Tip-toe gait.

What condition is associated with SBF1 p.Pro438Ser (c.1312C>T)?

SBF1 p.Pro438Ser (c.1312C>T) is associated with Tip-toe gait (ClinVar).

How common is SBF1 p.Pro438Ser (c.1312C>T) in the general population?

SBF1 p.Pro438Ser (c.1312C>T) is ultra-rare (popmax 0.0246%, nfe) (gnomAD).

What do computational predictors say about SBF1 p.Pro438Ser (c.1312C>T)?

AlphaMissense predicts likely benign (score 0.0588) — an in-silico prediction, not a clinical call.

SBF1 p.Pro438Ser

c.1312C>T · rs201645895 · VCV1394983

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0588 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0246%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Tip-toe gait

Computational evidence

Protein change
AlphaMissense	0.0588	likely benign
REVEL	0.112	moderately benign-leaning
SaProt	LLR -7.38	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 -0.52	GERP -4.4
Regional constraint	o/e 1.01	unconstrained · MANE · 19 kb · p 0.67 · regional, not allelic
Overall
CADD	3.552	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 P439S vs ClinVar P438S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0246% European (non-Finnish) · 290/1,179,968 alleles

Filtering AF 0.0222% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0213%

Overall 0.0204% 329/1,613,870 alleles · ultra-rare exomes 300/1,461,760 · genomes 29/152,110 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0422%	2,369
European (non-Finnish)grpmax	0.0246%	4,069
Remaining individualsnot grpmax-eligible	0.0192%	5,207

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro438Ser
Coding: c.1312C>T
MANE Select: NM_002972
dbSNP: rs201645895
Type: single nucleotide variant
Location: chr22:50465021 (GRCh38)
Gene constraint: LOEUF 0.381 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.72
Residue 439 UniProt numbering: the ddenn domain

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.Pro438Leu Uncertain significance ★★ ⚠ 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-pro438ser (accessed [today's date]).

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