Is SPTB p.Pro14Ser (c.40C>T) pathogenic?

SPTB p.Pro14Ser (c.40C>T) is classified Conflicting classifications of pathogenicity in SPTB (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.0969); Rare (popmax 0.142%, nfe).

How common is SPTB p.Pro14Ser (c.40C>T) in the general population?

SPTB p.Pro14Ser (c.40C>T) is rare (popmax 0.142%, nfe) (gnomAD).

What do computational predictors say about SPTB p.Pro14Ser (c.40C>T)?

AlphaMissense predicts likely benign (score 0.0969) — an in-silico prediction, not a clinical call.

SPTB p.Pro14Ser

c.40C>T · rs147059670 · VCV1298586

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0969 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.142%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0969	likely benign
REVEL	0.107	moderately benign-leaning
SaProt	LLR -5.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 18 kb · p 0.23 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.142% European (non-Finnish) · 1,677/1,180,038 alleles

Filtering AF 0.136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.134%

Overall 0.124% 1,995/1,614,170 alleles · rare exomes 1,775/1,461,840 · genomes 220/152,330 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.286%	350
European (non-Finnish)grpmax	0.142%	704
Remaining individualsnot grpmax-eligible	0.122%	822
Admixed American	0.075%	1,334
Middle Eastern	0.0166%	6,028
African / African-American	0.0133%	7,507
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869

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: SPTB
Protein: p.Pro14Ser
Coding: c.40C>T
MANE Select: NM_001355436
dbSNP: rs147059670
Type: single nucleotide variant
Location: chr14:64823055 (GRCh38)
Gene constraint: LOEUF 0.228 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.55 · 6 PDB
Residue 14: the 'disordered' region; the 'actin-binding' region

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

Similar variants

SPTB c.1064+1G>A Pathogenic ★★ same type
SPTB c.1341+1G>A Likely pathogenic ★★ same type
SPTB c.3764+1G>A Pathogenic/Likely pathogenic ★★ same type
SPTB c.474+1G>A Likely pathogenic ★★ same type
SPTB c.474+1G>T Pathogenic/Likely pathogenic ★★ same type
SPTB c.4843-1G>T Likely pathogenic ★★ same type
SPTB c.4973+5G>A Pathogenic/Likely pathogenic ★★ same type
SPTB c.5178+1G>A Likely pathogenic ★★ 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/sptb-p-pro14ser (accessed [today's date]).

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