Is EEFSEC p.Glu514Ter (c.1540G>T) pathogenic?

EEFSEC p.Glu514Ter (c.1540G>T) is classified Likely pathogenic in EEFSEC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-22). Ultra-rare (popmax 0.02%, eas); Associated with neurodevelopmental disorder with progressive spasticity and brain abnormalities.

How common is EEFSEC p.Glu514Ter (c.1540G>T) in the general population?

EEFSEC p.Glu514Ter (c.1540G>T) is ultra-rare (popmax 0.02%, eas) (gnomAD).

EEFSEC p.Glu514Ter

Q: What condition is associated with EEFSEC p.Glu514Ter (c.1540G>T)?

EEFSEC p.Glu514Ter (c.1540G>T) is associated with neurodevelopmental disorder with progressive spasticity and brain abnormalities (ClinVar).

c.1540G>T · VCV4856243

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, eas)

Conditions

neurodevelopmental disorder with progressive spasticity and brain abnormalities

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 7
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Overall
CADD	40.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% East Asian · 9/44,892 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00779%

Overall 0.000616% 9/1,461,876 alleles · ultra-rare

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: EEFSEC
Protein: p.Glu514Ter
Coding: c.1540G>T
MANE Select: NM_021937
Type: single nucleotide variant
Location: chr3:128358313 (GRCh38)
Gene constraint: LOEUF 1.345 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.98 · 4 PDB
Residue 514: a UniProt-annotated variant site (in nedpsb; likely pathogenic; decreased selenocysteine incorporation in selenoproteins)

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

Disease context

neurodevelopmental disorder with progressive spasticity and brain abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EEFSEC p.Arg285Gln Uncertain significance ★★ ⚠ same condition
EEFSEC p.Leu246Pro Uncertain significance ★ ⚠ same condition
EEFSEC p.Pro194Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
EEFSEC p.Cys426Ter Pathogenic same condition
EEFSEC p.Met1Val Pathogenic same condition
EEFSEC p.Val585fs Likely pathogenic ★ same condition
EEFSEC p.Arg424Gln Uncertain significance ★★ ⚠ same type
EEFSEC p.Phe463Leu Uncertain significance ★★ ⚠ same type

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/eefsec-p-glu514ter (accessed [today's date]).

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