Is EEFSEC p.Cys426Ter (c.1278C>A) pathogenic?

EEFSEC p.Cys426Ter (c.1278C>A) is classified Pathogenic in EEFSEC (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-02-25). Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with progressive spasticity and brain abnormalities.

How common is EEFSEC p.Cys426Ter (c.1278C>A) in the general population?

EEFSEC p.Cys426Ter (c.1278C>A) is absent from gnomAD v4.1 (gnomAD).

EEFSEC p.Cys426Ter

Q: What condition is associated with EEFSEC p.Cys426Ter (c.1278C>A)?

EEFSEC p.Cys426Ter (c.1278C>A) is associated with neurodevelopmental disorder with progressive spasticity and brain abnormalities (ClinVar).

c.1278C>A · VCV3764738

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 5 of 7
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 2.3, phastCons 1
Overall
CADD	37.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EEFSEC
Protein: p.Cys426Ter
Coding: c.1278C>A
MANE Select: NM_021937
Type: single nucleotide variant
Location: chr3:128341724 (GRCh38)
Gene constraint: LOEUF 1.345 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.98 · 4 PDB
Residue 426: 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.Glu514Ter Likely pathogenic ★ same condition
EEFSEC p.Leu246Pro Uncertain significance ★ ⚠ same condition
EEFSEC p.Pro194Thr Conflicting classifications of pathogenicity ★ ⚠ 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-cys426ter (accessed [today's date]).

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