Is SPEG p.Arg2139Leu (c.6416G>T) pathogenic?

SPEG p.Arg2139Leu (c.6416G>T) is classified Uncertain significance in SPEG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: likely benign (0.2943); Very rare (popmax 0.00845%, amr); Associated with Inborn genetic diseases.

What condition is associated with SPEG p.Arg2139Leu (c.6416G>T)?

SPEG p.Arg2139Leu (c.6416G>T) is associated with Inborn genetic diseases (ClinVar).

How common is SPEG p.Arg2139Leu (c.6416G>T) in the general population?

SPEG p.Arg2139Leu (c.6416G>T) is very rare (popmax 0.00845%, amr) (gnomAD).

What do computational predictors say about SPEG p.Arg2139Leu (c.6416G>T)?

AlphaMissense predicts likely benign (score 0.2943) — an in-silico prediction, not a clinical call.

SPEG p.Arg2139Leu

c.6416G>T · VCV4173418

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2943 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00845%, amr)

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	0.2943	likely benign
REVEL	0.379	indeterminate
SaProt	—	not scored · why
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	22.9	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 0.00845% Admixed American · 5/59,170 alleles

Filtering AF 0.00327% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00209%

Overall 0.00144% 23/1,597,596 alleles · very rare exomes 22/1,445,548 · genomes 1/152,048 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00845%	11,834
Remaining individualsnot grpmax-eligible	0.00322%	31,045
European (non-Finnish)	0.00136%	73,587

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.Arg2139Leu
Coding: c.6416G>T
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-arg2139leu (accessed [today's date]).

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