Is EEFSEC p.Arg285Gln (c.854G>A) pathogenic?

EEFSEC p.Arg285Gln (c.854G>A) is classified Uncertain significance in EEFSEC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-15). AlphaMissense: likely pathogenic (0.9756); Rare (popmax 0.13%, nfe); Associated with neurodevelopmental disorder with progressive spasticity and brain abnormalities.

How common is EEFSEC p.Arg285Gln (c.854G>A) in the general population?

EEFSEC p.Arg285Gln (c.854G>A) is rare (popmax 0.13%, nfe) (gnomAD).

What do computational predictors say about EEFSEC p.Arg285Gln (c.854G>A)?

AlphaMissense predicts likely pathogenic (score 0.9756) — an in-silico prediction, not a clinical call.

EEFSEC p.Arg285Gln

Q: What condition is associated with EEFSEC p.Arg285Gln (c.854G>A)?

EEFSEC p.Arg285Gln (c.854G>A) is associated with neurodevelopmental disorder with progressive spasticity and brain abnormalities (ClinVar).

c.854G>A · rs140543627 · VCV2305857

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9756 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.13%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with progressive spasticity and brain abnormalities

Computational evidence

Protein change
AlphaMissense	0.9756	likely pathogenic
REVEL	0.677	pathogenic-leaning
SaProt	LLR -14.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 255 kb · p 0.039 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.13% European (non-Finnish) · 1,531/1,180,014 alleles

Filtering AF 0.124% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.122%

Overall 0.103% 1,655/1,614,144 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.13%	771
Remaining individualsnot grpmax-eligible	0.096%	1,042
Admixed American	0.0533%	1,876
African / African-American	0.0306%	3,263
Middle Eastern	0.0165%	6,062
South Asian	0.00659%	15,179
East Asian	0.00223%	44,876
Finnishnot grpmax-eligible	0.00156%	64,030

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.Arg285Gln
Coding: c.854G>A
MANE Select: NM_021937
dbSNP: rs140543627
Type: single nucleotide variant
Location: chr3:128341300 (GRCh38)
Gene constraint: LOEUF 1.345 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.98 · 4 PDB
Residue 285: a UniProt-annotated variant site (in nedpsb; likely pathogenic; decreased selenocysteine incorporation in selenoproteins); a β-strand

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.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
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-arg285gln (accessed [today's date]).

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