Is SPEG p.Pro2825= (c.8475C>A) pathogenic?

SPEG p.Pro2825= (c.8475C>A) is classified Likely benign in SPEG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-17). Ultra-rare (popmax 0.0165%, mid).

How common is SPEG p.Pro2825= (c.8475C>A) in the general population?

SPEG p.Pro2825= (c.8475C>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

SPEG p.Pro2825=

c.8475C>A · rs374088448 · VCV1662260

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -1.2	GERP -2.9
Overall
CADD	0.74	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.00625% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00112% 18/1,612,276 alleles · ultra-rare exomes 8/1,460,488 · genomes 10/151,788 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
African / African-American	0.012%	8,306
Admixed American	0.00334%	29,976
South Asian	0.0011%	91,024
European (non-Finnish)	0.000424%	235,811

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.Pro2825=
Coding: c.8475C>A
MANE Select: NM_005876
dbSNP: rs374088448
Type: single nucleotide variant
Location: chr2:219489493 (GRCh38)

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

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-pro2825 (accessed [today's date]).

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