Is SPEG p.Pro751Leu (c.2252C>T) pathogenic?

SPEG p.Pro751Leu (c.2252C>T) is classified Uncertain significance in SPEG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-02-22). AlphaMissense: likely pathogenic (0.651); Very rare (popmax 0.00883%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SPEG p.Pro751Leu (c.2252C>T)?

SPEG p.Pro751Leu (c.2252C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SPEG p.Pro751Leu (c.2252C>T) in the general population?

SPEG p.Pro751Leu (c.2252C>T) is very rare (popmax 0.00883%, nfe) (gnomAD).

What do computational predictors say about SPEG p.Pro751Leu (c.2252C>T)?

AlphaMissense predicts likely pathogenic (score 0.651) — an in-silico prediction, not a clinical call.

SPEG p.Pro751Leu

c.2252C>T · rs369116326 · VCV2139701

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.651 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00883%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.651	likely pathogenic
REVEL	0.489	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 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 27 kb · p 0.32 · regional, not allelic
Overall
CADD	24.7	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 0.00883% European (non-Finnish) · 104/1,177,178 alleles

Filtering AF 0.00743% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00694%

Overall 0.00678% 109/1,607,350 alleles · very rare exomes 104/1,455,266 · genomes 5/152,084 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00883%	11,319
Remaining individualsnot grpmax-eligible	0.00482%	20,735
African / African-American	0.00134%	74,684
South Asian	0.00111%	90,116

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.Pro751Leu
Coding: c.2252C>T
MANE Select: NM_005876
dbSNP: rs369116326
Type: single nucleotide variant
Location: chr2:219451274 (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.Pro751Ser 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-pro751leu (accessed [today's date]).

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