Is SPEG p.Pro973= (c.2919C>T) pathogenic?

SPEG p.Pro973= (c.2919C>T) is classified Likely benign in SPEG (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-18). Very rare (popmax 0.00111%, sas).

How common is SPEG p.Pro973= (c.2919C>T) in the general population?

SPEG p.Pro973= (c.2919C>T) is very rare (popmax 0.00111%, sas) (gnomAD).

SPEG p.Pro973=

c.2919C>T · VCV4960028

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.85	GERP 0.16, phastCons 1
Overall
CADD	9.389	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00111% South Asian · 1/90,444 alleles

Overall 0.000125% 2/1,594,078 alleles · very rare exomes 1/1,441,844 · genomes 1/152,234 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00111%	90,444
European (non-Finnish)	8.54e-05%	1,171,379

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.Pro973=
Coding: c.2919C>T
MANE Select: NM_005876
Type: single nucleotide variant
Location: chr2:219467211 (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

Similar variants

SPEG p.Pro973Ser Uncertain significance ★ same residue
SPEG p.Arg1467Ter Likely pathogenic ★★ same type
SPEG p.Ser131Ter Pathogenic/Likely pathogenic ★★ same type
SPEG c.3301+5G>A Uncertain significance ★★ same type
SPEG c.478+5G>A Uncertain significance ★★ same type
SPEG p.Ala121Thr Uncertain significance ★★ same type
SPEG p.Ala1249Thr Uncertain significance ★★ ⚠ same type
SPEG p.Ala1334Val Uncertain significance ★★ ⚠ 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/speg-p-pro973 (accessed [today's date]).

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