Is SPEG p.Pro973Ser (c.2917C>T) pathogenic?

SPEG p.Pro973Ser (c.2917C>T) is classified Uncertain significance in SPEG (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-14). AlphaMissense: likely benign (0.2863); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SPEG p.Pro973Ser (c.2917C>T)?

SPEG p.Pro973Ser (c.2917C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SPEG p.Pro973Ser (c.2917C>T) in the general population?

SPEG p.Pro973Ser (c.2917C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SPEG p.Pro973Ser (c.2917C>T)?

AlphaMissense predicts likely benign (score 0.2863) — an in-silico prediction, not a clinical call.

SPEG p.Pro973Ser

c.2917C>T · VCV3448374

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2863 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2863	likely benign
REVEL	0.328	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 1.3, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 21 kb · p 4.1e-17 · regional, not allelic
Overall
CADD	26.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SPEG
Protein: p.Pro973Ser
Coding: c.2917C>T
MANE Select: NM_005876
Type: single nucleotide variant
Location: chr2:219467209 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI <0.01 (gnomAD)
Residue 973: the ig-like 4 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.Pro973= Likely benign ★ 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-pro973ser (accessed [today's date]).

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