Is SPEG p.Pro751Ser (c.2251C>T) pathogenic?

SPEG p.Pro751Ser (c.2251C>T) is classified Uncertain significance in SPEG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-19). AlphaMissense: likely pathogenic (0.6764); Very rare (popmax 0.0017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SPEG p.Pro751Ser (c.2251C>T)?

SPEG p.Pro751Ser (c.2251C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SPEG p.Pro751Ser (c.2251C>T) in the general population?

SPEG p.Pro751Ser (c.2251C>T) is very rare (popmax 0.0017%, nfe) (gnomAD).

What do computational predictors say about SPEG p.Pro751Ser (c.2251C>T)?

AlphaMissense predicts likely pathogenic (score 0.6764) — an in-silico prediction, not a clinical call.

SPEG p.Pro751Ser

c.2251C>T · rs376130056 · VCV1919063

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6764 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0017%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6764	likely pathogenic
REVEL	0.491	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.46, phastCons 0.99
Regional constraint	o/e 0.97	unconstrained · MANE · 27 kb · p 0.32 · regional, not allelic
Overall
CADD	21.6	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 0.0017% European (non-Finnish) · 20/1,177,252 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000902%

Overall 0.00124% 20/1,607,502 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: SPEG
Protein: p.Pro751Ser
Coding: c.2251C>T
MANE Select: NM_005876
dbSNP: rs376130056
Type: single nucleotide variant
Location: chr2:219451273 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI <0.01 (gnomAD)
Residue 751: the ig-like 2 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.Pro751Leu Uncertain significance ★★ same residue
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

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-pro751ser (accessed [today's date]).

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