Is EEF1A2 p.Ala461Val (c.1382C>T) pathogenic?

EEF1A2 p.Ala461Val (c.1382C>T) is classified Uncertain significance in EEF1A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-19). AlphaMissense: likely benign (0.1166); Very rare (popmax 0.000189%, nfe); Associated with developmental and epileptic encephalopathy, 33.

What condition is associated with EEF1A2 p.Ala461Val (c.1382C>T)?

EEF1A2 p.Ala461Val (c.1382C>T) is associated with developmental and epileptic encephalopathy, 33 (ClinVar).

How common is EEF1A2 p.Ala461Val (c.1382C>T) in the general population?

EEF1A2 p.Ala461Val (c.1382C>T) is very rare (popmax 0.000189%, nfe) (gnomAD).

What do computational predictors say about EEF1A2 p.Ala461Val (c.1382C>T)?

AlphaMissense predicts likely benign (score 0.1166) — an in-silico prediction, not a clinical call.

EEF1A2 p.Ala461Val

Q: How is Non-specific early-onset epileptic encephalopathy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1382C>T · rs757556226 · VCV384354

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1166 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000189%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 33

Computational evidence

Protein change
AlphaMissense	0.1166	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -10.31	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	Δ0.30	donor gain · deltas
Pangolin	Δ0.81	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 8.1	GERP 0.62, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 108 bp · p 0.00057 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000189% European (non-Finnish) · 2/1,056,070 alleles

Filtering AF 3.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.2e-05%

Overall 0.000218% 3/1,377,664 alleles · very rare exomes 3/1,227,098 · genomes 0/150,566 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00418%	23,904
European (non-Finnish)grpmax	0.000189%	528,036

Ashkenazi Jewish 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: EEF1A2
Protein: p.Ala461Val
Coding: c.1382C>T
MANE Select: NM_001958
dbSNP: rs757556226
Type: single nucleotide variant
Location: chr20:63488308 (GRCh38)
Gene constraint: LOEUF 0.314 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.70 · 2 PDB
Residue 461: the 'disordered' region

Full EEF1A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy, 33 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Non-specific early-onset epileptic encephalopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: Infancy, Neonatal

Similar variants

EEF1A2 p.Ala461= Likely benign ★★ same residue
EEF1A2 p.Arg266Trp Pathogenic/Likely pathogenic ★★ same condition
EEF1A2 p.Arg423Cys Pathogenic/Likely pathogenic ★★ same condition
EEF1A2 p.Arg69Cys Pathogenic ★★ same condition
EEF1A2 p.Asp91Asn Pathogenic ★★ ⚠ same condition
EEF1A2 p.Asp97Asn Pathogenic/Likely pathogenic ★★ same condition
EEF1A2 p.Glu122Lys Pathogenic/Likely pathogenic ★★ same condition
EEF1A2 p.Glu124Lys Pathogenic/Likely 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/eef1a2-p-ala461val (accessed [today's date]).

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