Is SPEG p.Pro1306Ser (c.3916C>T) pathogenic?

SPEG p.Pro1306Ser (c.3916C>T) is classified Uncertain significance in SPEG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-13). AlphaMissense: likely pathogenic (0.6824); Very rare (popmax 0.0011%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SPEG p.Pro1306Ser (c.3916C>T)?

SPEG p.Pro1306Ser (c.3916C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SPEG p.Pro1306Ser (c.3916C>T) in the general population?

SPEG p.Pro1306Ser (c.3916C>T) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about SPEG p.Pro1306Ser (c.3916C>T)?

AlphaMissense predicts likely pathogenic (score 0.6824) — an in-silico prediction, not a clinical call.

SPEG p.Pro1306Ser

c.3916C>T · VCV3714034

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6824 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6824	likely pathogenic
REVEL	0.464	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.9, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 21 kb · p 4.1e-17 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,179,986 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000806% 13/1,613,654 alleles · very rare exomes 11/1,461,434 · genomes 2/152,220 · joint denominator

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: SPEG
Protein: p.Pro1306Ser
Coding: c.3916C>T
MANE Select: NM_005876
Type: single nucleotide variant
Location: chr2:219472307 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI <0.01 (gnomAD)
Residue 1306: the fibronectin type-iii 1 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SPEG p.Ala1249Thr Uncertain significance ★★ ⚠ same condition
SPEG p.Ala1334Val Uncertain significance ★★ ⚠ same condition
SPEG p.Ala1628Val Uncertain significance ★★ same condition
SPEG p.Ala1686Thr Uncertain significance ★★ ⚠ same condition
SPEG p.Ala199Val Uncertain significance ★★ ⚠ same condition
SPEG p.Ala220Ser Uncertain significance ★★ ⚠ same condition
SPEG p.Ala241Thr Uncertain significance ★★ ⚠ same condition
SPEG p.Ala291Gly Uncertain significance ★★ ⚠ 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/speg-p-pro1306ser (accessed [today's date]).

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