Is EEF2K p.Gly654Ser (c.1960G>A) pathogenic?

EEF2K p.Gly654Ser (c.1960G>A) is classified Uncertain significance in EEF2K (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-27). AlphaMissense: likely benign (0.2112); Ultra-rare (popmax 0.0136%, eas).

How common is EEF2K p.Gly654Ser (c.1960G>A) in the general population?

EEF2K p.Gly654Ser (c.1960G>A) is ultra-rare (popmax 0.0136%, eas) (gnomAD).

What do computational predictors say about EEF2K p.Gly654Ser (c.1960G>A)?

AlphaMissense predicts likely benign (score 0.2112) — an in-silico prediction, not a clinical call.

EEF2K p.Gly654Ser

c.1960G>A · VCV3843498

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2112 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0136%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2112	likely benign
REVEL	0.357	indeterminate
SaProt	LLR -5.64	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.24	donor loss at this position · masked 0 · deltas
Constraint at this position
Conservation	phyloP 9.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 58 kb · p 0.22 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0136% East Asian · 6/44,250 alleles

Filtering AF 0.00586% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00398%

Overall 0.00392% 63/1,607,296 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0747%	1,339
East Asiangrpmax	0.0136%	7,375
Admixed American	0.0119%	8,432
Remaining individualsnot grpmax-eligible	0.00321%	31,105
South Asian	0.00223%	44,920
European (non-Finnish)	0.00195%	51,176
Finnishnot grpmax-eligible	0.00156%	63,954

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: EEF2K
Protein: p.Gly654Ser
Coding: c.1960G>A
MANE Select: NM_013302
Type: single nucleotide variant
Location: chr16:22280268 (GRCh38)
Gene constraint: LOEUF 0.896 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.36 · 10 PDB

Full EEF2K gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EEF2K p.Gly654Arg Uncertain significance ★ ⚠ same residue
EEF2K p.Ala158Asp Uncertain significance ★ ⚠ same type
EEF2K p.Ala164Thr Uncertain significance ★ ⚠ same type
EEF2K p.Ala169Val Uncertain significance ★ ⚠ same type
EEF2K p.Ala306Val Uncertain significance ★ ⚠ same type
EEF2K p.Ala313Asp Uncertain significance ★ ⚠ same type
EEF2K p.Ala558Thr Uncertain significance ★ ⚠ same type
EEF2K p.Ala617Val 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/eef2k-p-gly654ser (accessed [today's date]).

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