Is SPEG p.Arg2139Gln (c.6416G>A) pathogenic?

SPEG p.Arg2139Gln (c.6416G>A) is classified Uncertain significance in SPEG (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-11). AlphaMissense: likely benign (0.1358); Very rare (popmax 0.0011%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SPEG p.Arg2139Gln (c.6416G>A)?

SPEG p.Arg2139Gln (c.6416G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SPEG p.Arg2139Gln (c.6416G>A) in the general population?

SPEG p.Arg2139Gln (c.6416G>A) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about SPEG p.Arg2139Gln (c.6416G>A)?

AlphaMissense predicts likely benign (score 0.1358) — an in-silico prediction, not a clinical call.

SPEG p.Arg2139Gln

c.6416G>A · VCV3322112

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1358 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1358	likely benign
REVEL	0.104	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 9.8	GERP 1.2, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 7,108 bp · p 0.064 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,177,400 alleles

Filtering AF 0.000616% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000475%

Overall 0.000814% 13/1,597,596 alleles · very rare exomes 12/1,445,548 · genomes 1/152,048 · joint denominator

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.Arg2139Gln
Coding: c.6416G>A
MANE Select: NM_005876
Type: single nucleotide variant
Location: chr2:219483879 (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-arg2139gln (accessed [today's date]).

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