Is SPEG p.Pro1995Arg (c.5984C>G) pathogenic?

SPEG p.Pro1995Arg (c.5984C>G) is classified Conflicting classifications of pathogenicity in SPEG (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-29). AlphaMissense: likely benign (0.0866); Rare (popmax 0.104%, mid); Associated with Inborn genetic diseases.

What condition is associated with SPEG p.Pro1995Arg (c.5984C>G)?

SPEG p.Pro1995Arg (c.5984C>G) is associated with Inborn genetic diseases (ClinVar).

How common is SPEG p.Pro1995Arg (c.5984C>G) in the general population?

SPEG p.Pro1995Arg (c.5984C>G) is rare (popmax 0.104%, mid) (gnomAD).

What do computational predictors say about SPEG p.Pro1995Arg (c.5984C>G)?

AlphaMissense predicts likely benign (score 0.0866) — an in-silico prediction, not a clinical call.

SPEG p.Pro1995Arg

c.5984C>G · rs749216092 · VCV1650640

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0866 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.104%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

⚠ 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
AlphaMissense	0.0866	likely benign
REVEL	0.141	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 4.8	GERP 0.16, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 7,108 bp · p 0.064 · regional, not allelic
Overall
CADD	18.5	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 0.104% Middle Eastern · 5/4,824 alleles

Filtering AF 0.0557% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0505%

Overall 0.0151% 231/1,532,674 alleles · rare exomes 209/1,380,546 · genomes 22/152,128 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.326%	307
Middle Easterngrpmax	0.104%	965
South Asian	0.0702%	1,425
Remaining individualsnot grpmax-eligible	0.0353%	2,829
European (non-Finnish)	0.00479%	20,880
African / African-American	0.00412%	24,296
Admixed American	0.00211%	47,432

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro1995Arg
Coding: c.5984C>G
MANE Select: NM_005876
dbSNP: rs749216092
Type: single nucleotide variant
Location: chr2:219483447 (GRCh38)

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

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-pro1995arg (accessed [today's date]).

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