Is EEFSEC p.Val585fs (c.1751_1752dup) pathogenic?

EEFSEC p.Val585fs (c.17511752dup) is classified Likely pathogenic in EEFSEC (ClinVar, Single submitter, 2 submitters; last evaluated 2024-04-09). Very rare (popmax 0.0011%, sas); Associated with infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly.

What condition is associated with EEFSEC p.Val585fs (c.1751_1752dup)?

EEFSEC p.Val585fs (c.1751_1752dup) is associated with infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly, neurodevelopmental disorder with progressive spasticity and brain abnormalities (ClinVar).

How common is EEFSEC p.Val585fs (c.1751_1752dup) in the general population?

EEFSEC p.Val585fs (c.1751_1752dup) is very rare (popmax 0.0011%, sas) (gnomAD).

EEFSEC p.Val585fs

c.1751_1752dup · rs765639766 · VCV3067139

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (7 of 7) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.59	GERP -2.7, phastCons 1
Overall
CADD	33.0	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 0.0011% South Asian · 1/90,650 alleles

Overall 6.21e-05% 1/1,610,650 alleles · very rare exomes 0/1,458,376 · genomes 1/152,274 · 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: EEFSEC
Protein: p.Val585fs
Coding: c.1751_1752dup
MANE Select: NM_021937
dbSNP: rs765639766
Type: Duplication
Location: chr3:128408217 (GRCh38)
Gene constraint: LOEUF 1.345 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.98 · 4 PDB
Residue 585: 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

infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neurodevelopmental disorder with progressive spasticity and brain abnormalities

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.Cys426Ter Pathogenic same condition
EEFSEC p.Met1Val Pathogenic same condition

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-val585fs (accessed [today's date]).

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