Is SPEG p.Ser2014Arg (c.6040A>C) pathogenic?

SPEG p.Ser2014Arg (c.6040A>C) is classified Uncertain significance in SPEG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-20). AlphaMissense: likely pathogenic (0.8535); Ultra-rare (popmax 0.0248%, eas); Associated with Inborn genetic diseases.

What condition is associated with SPEG p.Ser2014Arg (c.6040A>C)?

SPEG p.Ser2014Arg (c.6040A>C) is associated with Inborn genetic diseases (ClinVar).

How common is SPEG p.Ser2014Arg (c.6040A>C) in the general population?

SPEG p.Ser2014Arg (c.6040A>C) is ultra-rare (popmax 0.0248%, eas) (gnomAD).

What do computational predictors say about SPEG p.Ser2014Arg (c.6040A>C)?

AlphaMissense predicts likely pathogenic (score 0.8535) — an in-silico prediction, not a clinical call.

SPEG p.Ser2014Arg

c.6040A>C · rs1000883349 · VCV2201678

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8535 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0248%, eas)

Missense predictors

1/2 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	0.8535	likely pathogenic
REVEL	0.076	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 9	GERP 1.3, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 7,108 bp · p 0.064 · regional, not allelic
Overall
CADD	25.1	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 0.0248% East Asian · 9/36,284 alleles

Filtering AF 0.0129% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00959%

Overall 0.00302% 43/1,422,400 alleles · ultra-rare exomes 31/1,270,424 · genomes 12/151,976 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0457%	2,186
East Asiangrpmax	0.0248%	4,032
African / African-American	0.00898%	11,133
Admixed American	0.00325%	30,782
European (non-Finnish)	0.000182%	549,653

Remaining individuals 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.Ser2014Arg
Coding: c.6040A>C
MANE Select: NM_005876
dbSNP: rs1000883349
Type: single nucleotide variant
Location: chr2:219483503 (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-ser2014arg (accessed [today's date]).

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